Pyridine derivatives and pyrimidine derivatives (3)

ABSTRACT

A compound represented by the following formula, a salt thereof or a hydrate of the foregoing has an excellent hepatocyte growth factor receptor (HGFR) inhibitory activity, and exhibits anti-tumor activity, angiogenesis inhibitory activity and cancer metastasis inhibitory activity. 
                         
[R 1  represents a 3- to 10-membered non-aromatic heterocyclic group or the like; R 2  and R 3  represent hydrogen; R 4 , R 5 , R 6 , and R 7  may be the same or different and each represents hydrogen, halogen, C 1-6  alkyl or the like; R 8  represents hydrogen or the like; R 9  represents a 3- to 10-membered non-aromatic heterocyclic group or the like; n represents an integer of 1 or 2; X represents —CH═, nitrogen or the like.]

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 60/710,671, filed on Aug. 24, 2005, which is herein incorporated byreference in its entirety for all purposes.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a novel pyridine derivative andpyrimidine derivative, a salt thereof or a hydrate of the foregoing,having inhibitory activity against hepatocyte growth factor receptor,anti-tumor activity, inhibitory activity against angiogenesis,inhibitory activity against cancer metastasis or the like.

2. Related Background of the Invention

Overexpression of hepatocyte growth factor receptor (hereafter referredto as “HGFR”) is reported in various kinds of tumors such as apancreatic cancer, a gastric cancer, a colorectal cancer, a breastcancer, a prostate cancer, a lung cancer, a renal cancer, a brain tumoror an ovarian cancer (non-patent document 1). HGFR expressed in thesecancer cells is considered to be involved in cancer malignancy (aberrantgrowth, invasion or enhanced metastasis), because HGFR causeautophosphorylation of intracellular tyrosine kinase constitutively orupon stimulation by hepatocyte growth factor (hereafter referred to asHGF).

It is also reported that HGFR is expressed in vascular endothelial cellsand is involved in tumor angiogenesis since HGF stimulates HGFR tofacilitate proliferation and migration of vascular endothelial cells(non-patent document 2).

Furthermore, NK4, an antagonistic peptide for HGF, is reported to blockHGF-HGFR signal to inhibit invasion of cancer cells and tumorangiogenesis (non-patent documents 3 and 4).

Therefore, a compound having inhibitory activity against HGFR isexpected to be useful as an anti-tumor agent, an angiogenesis inhibitoror an inhibitor for cancer metastasis.

With regard to documents disclosing a low molecular weight compoundhaving inhibitory activity against HGFR, the patent documents 1 to 11are listed. However, the patent documents 1 and 2 disclose indolinonederivatives; the patent documents 3 and 4 disclose quinoline derivativesand quinazoline derivatives; the patent documents 5 and 6 discloseimidazole derivatives; the patent document 7 discloses aminopyridinederivatives and aminopyrazine derivatives; the patent document 8discloses triazolopyrazine derivatives and imidazopyrazine derivatives;the patent document 9 discloses tetracyclic derivatives; the patentdocument 10 discloses triazolotriazine derivatives; the patent document11 discloses pyrrole derivatives; therefore the compounds disclosed inthese documents are obviously different in the structure from pyridinederivatives and pyrimidine derivatives according to the presentinvention.

The patent documents 12 and 13 disclose pyridine derivatives andpyrimidine derivatives similar in the structure to the compoundsaccording to the present invention. The patent documents 12 and 13,however, do not disclose inhibitory activity against HGFR of thecompounds disclosed in the patent documents 12 and 13 as well as thecompounds according to the present invention.

-   -   [Patent document 1] WO 02/096361    -   [Patent document 2] WO 2005/005378    -   [Patent document 3] WO 03/000660    -   [Patent document 4] WO 2005/030140    -   [Patent document 5] WO 03/087026    -   [Patent document 6] WO 2005/040154    -   [Patent document 7] WO 2004/076412    -   [Patent document 8] WO 2005/004607    -   [Patent document 9] WO 2005/004808    -   [Patent document 10] WO 2005/010005    -   [Patent document 11] WO 2005/016920    -   [Patent document 12] WO 02/032872    -   [Patent document 13] WO 2005/005389    -   [Non-patent document 1] Oncology Reports, 5, 1013-1024 (1998)    -   [Non-patent document 2] Advances in Cancer Research, 67, 257-279        (1995)    -   [Non-patent document 3] British Journal of Cancer, 84, 864-873        (2001)    -   [Non-patent document 4] Cancer Sci., 94, 321-327 (2003)

SUMMARY OF THE INVENTION

An object of the present invention is to provide a compound showinganti-tumor activity, inhibitory activity against angiogenesis orinhibitory activity against cancer metastasis by inhibiting cellularaberrant growth, morphological change and hypermobility via HGFR invivo.

As a result of diligent studies in view of the above situation, thepresent inventors have succeeded in synthesizing novel pyridinederivatives and pyrimidine derivatives represented by the formula (I),salts thereof or hydrates of the foregoing, found out that thecompounds, salts thereof or hydrates of the foregoing have excellentinhibitory activity against HGFR and also exhibit anti-tumor activity,inhibitory activity against angiogenesis or inhibitory activity againstcancer metastasis, and completed the present invention.

Namely, the present invention provides [1] to [35] below:

-   [1] A compound represented by the following formula, a salt thereof    or a hydrate of the foregoing:

-   -   wherein R¹ represents a 3- to 10-membered non-aromatic        heterocyclic group wherein the group is limited to a group        having nitrogen as a ring constituent atom and the nitrogen        having a bonding hand, or a group represented by the formula        —NR^(11a)R^(11b), wherein R^(11a) and R^(11b) may be the same or        different and each represents hydrogen, C₁₋₆ alkyl, C₃₋₆        alkenyl, C₃₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl or a 4- to 10-membered non-aromatic        heterocyclic group, and R^(11a) and R^(11b) may be substituted        with a substituent selected from Substituent Group A or        Substituent Group B and R¹ may be substituted with a substituent        selected from Substituent Group A or Substituent Group B;    -   R² and R³ represent hydrogen;    -   R⁴, R⁵, R⁶ and R⁷ may be the same or different and each        represents hydrogen, halogen, hydroxyl, cyano, trifluoromethyl,        C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, amino,        mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino or a group represented        by the formula —CO—R¹², wherein R¹² represents hydrogen,        hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino        or di-C₁₋₆ alkylamino;    -   R⁸ represents hydrogen or C₁₋₆ alkyl;    -   R⁹ represents a 3- to 10-membered non-aromatic heterocyclic        group wherein the group is limited to a group having nitrogen as        a ring constituent atom and the nitrogen having a bonding hand,        or a group represented by the formula —NR^(11a)R^(11b), wherein        R^(11a) and R^(11b) represent the same meaning as described        above and R⁹ may be substituted with a substituent selected from        Substituent Group A or Substituent Group B;    -   n represents an integer of 1 or 2; and    -   X represents a group represented by the formula —C(R¹⁰)═ or        nitrogen, wherein R¹⁰ represents hydrogen, halogen, cyano, C₁₋₆        alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or a group represented by the        formula —CO—R¹², wherein R¹² represents the same meaning as        recited above;    -   wherein Substituent Group A consists of halogen, hydroxyl,        mercapto, nitro, cyano and oxo;    -   wherein Substituent Group B consists of C₁₋₆ alkyl, C₂₋₆        alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, a 3- to 10-membered non-aromatic        heterocyclic group, C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₃₋₆        alkynyloxy, C₃₋₁₀ cycloalkoxy, C₆₋₁₀ aryloxy, 5- to 10-membered        heteroaryloxy, 4- to 10-membered non-aromatic heterocyclicoxy,        C₁₋₆ alkylthio, C₃₋₆ alkenylthio, C₃₋₆ alkynylthio, C₃₋₁₀        cycloalkylthio, C₆₋₁₀ arylthio, 5- to 10-membered        heteroarylthio, 4- to 10-membered non-aromatic heterocyclicthio        and a group represented by the formula -T¹-T²-T³, and each group        in Substituent Group B may be substituted with a substituent        selected from Substituent Group C, wherein T¹ represents a        direct bond or C₁₋₆ alkylene, T² represents carbonyl, sulfinyl,        sulfonyl, a group represented by the formula —C(═O)—O—, a group        represented by the formula —O—C(═O)—, a group represented by the        formula —SO₂—O—, a group represented by the formula —O—SO₂—, a        group represented by the formula —NR^(T1)—, a group represented        by the formula —C(═O)—NR^(T1)—, a group represented by the        formula —NR^(T1)—C(═O)—, a group represented by the formula        —SO₂—NR^(T1)— or a group represented by the formula        —NR^(T1)—SO₂—, T³ represents hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl,        C₃₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl or a 4- to 10-membered non-aromatic heterocyclic        group, and R^(T1) represents hydrogen or C₁₋₆ alkyl; and    -   wherein Substituent Group C consists of halogen, hydroxyl,        mercapto, nitro, cyano, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆        alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, a 3- to 10-membered non-aromatic heterocyclic group,        C₁₋₆ alkoxy, C₁₋₆ alkylthio, mono-C₁₋₆ alkylamino and di-C₁₋₆        alkylamino.

-   [2] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a 3- to 10-membered non-aromatic    heterocyclic group optionally substituted with a substituent    selected from Substituent Group A or Substituent Group B recited in    [1], wherein the group is limited to a group having nitrogen as a    ring constituent atom and the nitrogen having a bonding hand.

-   [3] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    (II):

wherein a represents an integer of 1 to 4;or a group represented by the formula (III):

wherein b represents an integer of 1 to 3, and Z represents oxygen,sulfur, carbonyl, sulfonyl, or a group represented by the formula—NR^(Z)—, wherein R^(Z) represents hydrogen or C₁₋₆ alkyl, and thegroups represented by the formula (II) or (III) may be substituted witha substituent selected from Substituent Group A or Substituent Group Brecited in [1].

-   [4] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents azetidin-1-yl optionally    substituted with a substituent selected from Substituent Group D,    pyrrolidin-1-yl optionally substituted with a substituent selected    from Substituent Group D, piperidin-1-yl optionally substituted with    a substituent selected from Substituent Group D, azepan-1-yl    optionally substituted with a substituent selected from Substituent    Group D, piperazin-1-yl optionally substituted with a substituent    selected from Substituent Group D, diazepan-1-yl optionally    substituted with a substituent selected from Substituent Group D,    morpholin-4-yl optionally substituted with a substituent selected    from Substituent Group D, thiomorpholin-4-yl optionally substituted    with a substituent selected from Substituent Group D,    1,1-dioxothiomorpholin-4-yl optionally substituted with a    substituent selected from Substituent Group D,    -   wherein Substituent Group D consists of halogen, hydroxyl,        mercapto, cyano, formyl, oxo, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₁₋₆        alkoxy, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl        and a group represented by -T⁴-T⁵, wherein T⁴ represents        carbonyl or sulfonyl, and T⁵ represents C₁₋₆ alkyl, C₃₋₁₀        cycloalkyl, azetidinyl, pyrrolidinyl, piperidinyl, hydroxyl,        C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino or di-C₁₋₆ alkylamino,    -   where each group included in Substituent Group D may be        substituted with hydroxyl, C₁₋₆ alkyl, di-C₁₋₆ alkylamino,        azetidinyl or pyrrolidinyl.-   [5] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represent azetidin-1-yl optionally substituted    with a substituent selected from Substituent Group E,    pyrrolidin-1-yl optionally substituted with a substituent selected    from Substituent Group E, piperidin-1-yl optionally substituted with    a substituent selected from Substituent Group E, piperazin-1-yl    optionally substituted with a substituent selected from Substituent    Group E, diazepan-1-yl optionally substituted with a substituent    selected from Substituent Group E or morpholin-4-yl optionally    substituted with a substituent selected from Substituent Group E,    -   wherein Substituent Group E consists of methyl, ethyl,        dimethylamino, azetidinyl, pyrrolidinyl, piperidinyl and        piperazinyl,    -   where each group included in Substituent Group E may be        substituted with hydroxyl, methyl, dimethylamino, azetidinyl,        pyrrolidinyl or piperidinyl.-   [6] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents azetidin-1-yl optionally    substituted with a substituent selected from Substituent Group G,    pyrrolidin-1-yl optionally substituted with a substituent selected    from Substituent Group G, piperidin-1-yl optionally substituted with    a substituent selected from Substituent Group G or piperazin-1-yl    optionally substituted with a substituent selected from Substituent    Group G,    -   wherein Substituent Group G consists of dimethylamino,        azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,        dimethylaminomethyl, dimethylaminoethyl, azetidin-1-ylmethyl,        pyrrolidin-1-ylmethyl and piperidin-1-ylmethyl,    -   where each group included in Substituent Group G may be        substituted with methyl or dimethylamino.-   [6-1] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein R¹ represents azetidin-1-yl optionally    substituted with a substituent selected from Substituent Group G-1,    pyrrolidin-1-yl optionally substituted with a substituent selected    from Substituent Group G-1, piperidin-1-yl optionally substituted    with a substituent selected from Substituent Group G-1 or    piperazin-1-yl optionally substituted with a substituent selected    from Substituent Group G-1,    -   wherein Substituent Group G-1 consists of azetidinyl,        pyrrolidinyl, piperidinyl, piperazinyl, dimethylaminomethyl,        dimethylaminoethyl, azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl        and piperidin-1-ylmethyl,    -   where each group included in Substituent Group G-1 may be        substituted with methyl or dimethylamino.-   [6-2] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein R¹ represents azetidin-1-yl having    dimethylamino, pyrrolidin-1-yl having dimethylamino or    piperidin-1-yl having dimethylamino.-   [6-3] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein R¹ represents azetidin-1-yl optionally    substituted with a substituent selected from Substituent Group G-2,    pyrrolidin-1-yl substituted with a substituent selected from    Substituent Group G-2 or piperidin-1-yl substituted with a    substituent selected from Substituent Group G-2,    -   wherein Substituent Group G-2 consists of hydroxyl, methoxy,        hydroxymethyl and dimethylaminoacetoxy.        [6-4] A compound according to [1], a salt thereof or a hydrate        of the foregoing, wherein R¹ represents        [2-(dimethylamino)ethyl]piperazin-1-yl,        4-pyrrolidin-1-ylpiperidin-1-yl,        4-[(dimethylamino)methyl]piperidin-1-yl,        4-azetidin-1-ylpiperidin-1-yl,        4-[3-(dimethylamino)azetidin-1-yl]piperidin-1-yl,        4-(4-methylpiperazin-1-yl)piperidin-1-yl,        4-(1-methylpiperidin-4-yl)piperazin-1-yl,        4-(1-methylazetidin-3-yl)piperazin-1-yl,        4-(dimethylamino)piperidin-1-yl,        4-(azetidin-1-ylmethyl)piperidin-1-yl,        4-(pyrrolidin-1-ylmethyl)piperidin-1-yl,        (3S)-3-(dimethylamino)pyrrolidin-1-yl,        (3R)-3-(dimethylamino)pyrrolidin-1-yl, azetidin-1-yl,        pyrrolidin-1-yl, morpholin-4-yl, 4-methylpiperazin-1-yl,        3-hydroxyazetidin-1-yl, 1,3′-biazetidin-1′-yl,        3-(hydroxymethyl)azetidin-1-yl, 3-(dimethylamino)azetidin-1-yl,        3-[(dimethylamino)methyl]azetidin-1-yl, 4-hydroxypiperidin-1-yl,        4-(hydroxymethyl)piperidin-1-yl, (3R)-3-hydroxypyrrolidin-1-yl,        (3S)-3-hydroxypyrrolidin-1-yl,        3-(azetidin-1-ylmethyl)azetidin-1-yl or        3-(2-dimethylaminoacetoxy)azetidin-1-yl.-   [7] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —NR^(11a)R^(11b), wherein R^(11a) and R^(11b) represent the same    meaning as recited in [1].-   [8] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —NR^(11c)R^(11d), wherein R^(11c) represents hydrogen or C₁₋₆ alkyl,    and R^(11d) represents C₁₋₆ alkyl or a group represented by the    formula (IV):

wherein c represents an integer of 1 to 3, and Z¹ represents oxygen,sulfur, carbonyl, sulfonyl or a group represented by the formula—NR^(Z1)—, wherein R^(Z1) represents hydrogen or C₁₋₆ alkyl, and R^(11d)may be substituted with a substituent selected from Substituent Group Aor Substituent Group B recited in [1].

-   [9] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —NR^(11e)R^(11f), wherein R^(11e) represents hydrogen or C₁₋₆ alkyl,    and R^(11f) represents C₁₋₆ alkyl, pyrrolidin-3-yl, piperidin-3-yl,    piperidin-4-yl or tetrahydropyran-4-yl, and R^(11f) may be    substituted with a substituent selected from Substituent Group D    recited in [4].-   [10] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —NR^(11g)R^(11h), wherein R^(11g) represents hydrogen or methyl, and    R^(11h) represents n-propyl, n-butyl, pyrrolidin-3-yl,    piperidin-3-yl, piperidin-4-yl or tetrahydropyran-4-yl, and R^(11h)    may be substituted with a substituent selected from Substituent    Group F,    -   wherein Substituent Group F consists of methyl, ethyl, n-propyl,        acetyl, dimethylamino, diethylamino, azetidinyl, pyrrolidinyl        and piperazinyl,    -   where each group included in Substituent Group F may be        substituted with methyl or dimethylamino.-   [11] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —N(CH₃)R^(11i), wherein R^(11i) represents n-propyl, n-butyl,    pyrrolidin-3-yl or piperidin-4-yl, and R^(11i) may be substituted    with a substituent selected from Substituent Group H,    -   wherein Substituent Group H consists of dimethylamino,        diethylamino, dimethylaminoethyl, dimethylaminopropyl and        1-methylazetidin-3-yl.-   [12] A compound according to [1], a salt thereof or a hydrate of the    foregoing, wherein R¹ represents a group represented by the formula    —N(CH₃)R^(11j), wherein R^(11j) represents 1-methylpiperidin-4-yl or    1-ethylpiperidin-4-yl.-   [12-1] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein R¹ represents a group represented by the    formula —N(CH₃)R^(11k), wherein R^(11k) represents    3-(dimethylamino)propyl or 1-[2-(dimethylamino)ethyl]piperidin-4-yl.-   [12-2] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein R¹ represents    methyl(1-methylpiperidin-4-yl)amino,    (1-ethylpiperidin-4-yl)(methyl)amino,    [3-(dimethylamino)propyl](methyl)amino or    {1-[2-(dimethylamino)ethyl]piperidin-4-yl}(methyl)amino.-   [13] A compound according to any one of [1] to [12-2], a salt    thereof or a hydrate of the foregoing, wherein R⁴, R⁵, R⁶ and R⁷ may    be the same or different and each represents hydrogen, halogen or    C₁₋₆ alkyl.-   [14] A compound according to any one of [1] to [13], a salt thereof    or a hydrate of the foregoing, wherein R⁸ represents hydrogen.-   [15] A compound according to any one of [1] to [14], a salt thereof    or a hydrate of the foregoing, wherein X represents a group    represented by the formula —C(R^(10a))═, wherein R^(10a) represents    hydrogen, halogen or cyano.-   [16] A compound according to any one of [1] to [14], a salt thereof    or a hydrate of the foregoing, wherein X represents nitrogen.-   [17] A compound according to any one of [1] to [16], a salt thereof    or a hydrate of the foregoing, wherein n represents 1.-   [18] A compound according to any one of [1] to [17], a salt thereof    or a hydrate of the foregoing, wherein R⁹ represents mono-C₁₋₆    alkylamino optionally substituted with a substituent selected from    Substituent Group A or Substituent Group B recited in [1],    mono-C₃₋₁₀ to cycloalkylamino optionally substituted with a    substituent selected from Substituent Group A or Substituent Group B    recited in [1], mono-C₆₋₁₀ arylamino optionally substituted with a    substituent selected from Substituent Group A or Substituent Group B    recited in [1], mono-5- to 10-membered heteroarylamino optionally    substituted with a substituent selected from Substituent Group A or    Substituent Group B recited in [1] or mono-4- to 10-membered    non-aromatic heterocyclic amino optionally substituted with a    substituent selected from Substituent Group A or Substituent Group B    recited in [1].-   [19] A compound according to any one of [1] to [17], a salt thereof    or a hydrate of the foregoing, wherein R⁹ represents mono-C₃₋₁₀    cycloalkylamino optionally substituted with a substituent selected    from Substituent Group A or Substituent Group B recited in [1] or    mono-C₆₋₁₀ arylamino optionally substituted with a substituent    selected from Substituent Group A or Substituent Group B recited in    [1].-   [19-1] A compound according to any one of [1] to [17], a salt    thereof or a hydrate of the foregoing, wherein R⁹ represents    mono-C₃₋₁₀ cycloalkylamino optionally substituted with a substituent    selected from Substituent Group I or mono-C₆₋₁₀ arylamino optionally    substituted with a substituent selected from Substituent Group I,    -   wherein Substituent Group I consists of halogen,        trifluoromethyl, cyano, C₁₋₆ alkyl and C₁₋₆ alkoxy.-   [19-2] A compound according to any one of [1] to [17], a salt    thereof or a hydrate of the foregoing, wherein R⁹ represents    cyclopentylamino optionally substituted with a substituent selected    from Substituent Group I recited in [19-1], cyclohexylamino    optionally substituted with a substituent selected from Substituent    Group I recited in [19-1], cycloheptylamino optionally substituted    with a substituent selected from Substituent Group I recited in    [19-1] or phenylamino optionally substituted with a substituent    selected from Substituent Group I recited in [19-1].-   [19-3] A compound according to [1], a salt thereof or a hydrate of    the foregoing, wherein a compound represented by the formula (I) is-   (1)    N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (2)    N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (3)    N-(4-Fluorophenyl)-N′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide,-   (4)    N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (5)    N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (6)    N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (7)    N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (8)    N-(2-Fluoro-4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (9)    N-(2-Fluoro-4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (10)    N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (11)    N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (12)    N-(4-Fluorophenyl)-N′-(2-fluoro-4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide,-   (13)    N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (14)    N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (15)    N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (16)    N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (17)    N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-phenylcyclopropane-1,1-dicarboxamide,-   (18)    N-(4-{[2-({[(1-Ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (19)    N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (20)    N-(4-Fluorophenyl)-N′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide,-   (21)    N-{2-Fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (22)    N-[4-({2-[(1,3′-Biazetidin-1′-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (23)    N-(2-Fluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (24)    N-(4-{[2-({[3-(Dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (25)    N-[4-({2-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (26)    N-{2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (27)    N-(2-Fluoro-4-{[2-({[4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (28)    N-(2-Fluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (29)    N-(2-Fluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (30)    N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (31)    N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (32)    N-(2,5-Difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (33)    N-[2,5-Difluoro-4-({2-[({3-[(dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (34)    N-(2,5-Difluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (35)    N-{4-[(2-{[3-(Azetidin-1-ylmethyl)azetidin-1-ylcarbonyl]amino}pyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (36)    N-(2,5-Difluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (37)    N-{2,5-Difluoro-4-[(4-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyrimidin-6-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (38) N-[4-({4-[({3-[(Dimethylamino)methyl]azetidin    1-yl}carbonyl)amino]pyrimidin-6-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (39)    N-(2,5-Difluoro-4-{[4-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (40)    N-(2,5-Difluoro-4-{[4-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (41)    N-(2,5-Difluoro-4-{[4-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (42)    N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (43)    N-{2,5-Difluoro-4-[(2-{[(4-methylpiperazin-1-yl)carbonyl]amino}pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (44)    N-{2,5-Difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (45)    N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (46)    N-(2,5-Difluoro-4-{[2-({[3-(2-dimethylaminoacetoxy)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (47)    N-(2,5-Difluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide    or-   (48)    N-(2,5-Difluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.-   [20] A pharmaceutical composition comprising a compound according to    [1], a salt thereof or a hydrate of the foregoing.-   [21] An inhibitor against hepatocyte growth factor receptor,    comprising a compound according to [1], a salt thereof or a hydrate    of the foregoing.-   [22] An angiogenesis inhibitor comprising a compound according to    [1], a salt thereof or a hydrate of the foregoing.-   [23] An anti-tumor agent comprising a compound according to [1], a    salt thereof or a hydrate of the foregoing.-   [24] An anti-tumor agent according to [23], wherein tumor is a    pancreatic cancer, a gastric cancer, a colorectal cancer, a breast    cancer, a prostate cancer, a lung cancer, a renal cancer, a brain    tumor or an ovarian cancer.-   [25] An inhibitor against cancer metastasis, comprising a compound    according to [1], a salt thereof or a hydrate of the foregoing.-   [26] A prophylactic or therapeutic method for a disease for which    inhibition of hepatocyte growth factor receptor is effective,    comprising administering to a patient, a pharmacologically effective    dose of a compound according to [1], a salt thereof or a hydrate of    the foregoing.-   [27] A prophylactic or therapeutic method for a disease for which    angiogenesis inhibition is effective, comprising administering to a    patient, a pharmacologically effective dose of a compound according    to [1], a salt thereof or a hydrate of the foregoing.-   [28] A prophylactic or therapeutic method for a tumor, comprising    administering to a patient, a pharmacologically effective dose of a    compound according to [1], a salt thereof or a hydrate of the    foregoing.-   [29] A prophylactic or therapeutic method for a tumor according to-   [28], wherein tumor is a pancreatic cancer, a gastric cancer, a    colorectal cancer, a breast cancer, a prostate cancer, a lung    cancer, a renal cancer, a brain tumor or an ovarian cancer.-   [30] A prophylactic or therapeutic method for a cancer metastasis,    comprising administering to a patient, a pharmacologically effective    dose of a compound according to [1], a salt thereof or a hydrate of    the foregoing.-   [31] Use of a compound according to [1], a salt thereof or a hydrate    of the foregoing for the manufacture of an inhibitor against    hepatocyte growth factor receptor.-   [32] Use of a compound according to [1], a salt thereof or a hydrate    of the foregoing for the manufacture of an angiogenesis inhibitor.-   [33] Use of a compound according to [1], a salt thereof or a hydrate    of the foregoing for the manufacture of an anti-tumor agent.-   [34] Use according to [33], wherein tumor is a pancreatic cancer, a    gastric cancer, a colorectal cancer, a breast cancer, a prostate    cancer, a lung cancer, a renal cancer, a brain tumor or an ovarian    cancer.-   [35] Use of a compound according to [1], a salt thereof or a hydrate    of the foregoing for the manufacture of an inhibitor against cancer    metastasis.

EFFECT OF THE INVENTION

The compound according to the present invention has an inhibitoryactivity against HGFR tyrosine kinase (Pharmacological Test Examples 1and 3), and thus inhibits proliferation of human cancer cells caused byHGFR activation (Pharmacological Test Example 2). The compound accordingto the present invention also inhibits migration of human cancer cells(Pharmacological Test Example 4). Furthermore, the compound according tothe present invention inhibits proliferation of vascular endothelialcells via HGF-HGFR signal (Pharmacological Test Example 7).

Overexpression of HGFR is reported to involve in malignancy of cancer(overgrowth, invasion and enhanced metastasis) in a pancreatic cancer, agastric cancer, a colorectal cancer, a breast cancer, a prostate cancer,a lung cancer, a renal cancer, a brain tumor, an ovarian cancer and ablood cancer (Cancer Research, 54, 5775-5778 (1994); Biochemical andBiophysical Research Communication, 189, 227-232 (1992); Oncogene, 7,181-185 (1992); Cancer, 82, 1513-1520 (1998); J. Urology, 154, 293-298(1995); Oncology, 53, 392-397 (1996); Oncogene, 14, 2343-2350 (1999);Cancer Research, 57, 5391-5398 (1997); Pathology Oncology Research, 5,187-191 (1999); Clinical Cancer Research, 9, 181-187 (2003)).

Additionally, HGFR activation in vascular endothelial cells is reportedto facilitate tumor angiogenesis (Advances in Cancer Research, 67,257-279 (1995)).

Therefore, the compound according to the present invention which hasexcellent inhibitory activity against HGFR is useful as an anti-tumoragent, an inhibitor against angiogenesis or a cancer metastasisinhibitor against various kinds of cancers such as a pancreatic cancer,a gastric cancer, a colorectal cancer, a breast cancer, a prostatecancer, a lung cancer, a renal cancer, a brain tumor and an ovariancancer.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The symbols and terms as used herein will be defined and the presentinvention will be described in details below.

Several of the structural formulas for the compounds throughout thepresent specification represent only one isomeric form for convenience,but the invention encompasses any and all of the geometric isomers aswell as optical isomers based on asymmetric carbons, stereoisomers andtautomers, and mixtures of those isomers, which are implied by thestructures of the compounds, without being limited to any of theformulas shown for convenience. The compounds of the invention thereforeinclude all those having asymmetric carbons therein and existing inoptically active or racemic form, with no particular restrictions on theinvention. There are also no restrictions when polymorphic crystallineforms thereof exist, and the compounds may be in one crystalline form ora mixture of different crystalline forms, while anhydrates and hydratesof the compounds of the invention are also included.

The so-called metabolite, a compound which a compound according to thepresent invention is metabolized in a living body through oxidation,reduction, hydrolysis, conjugation and the others to provide, and theso-called prodrug, a compound which is metabolized in a living bodythrough oxidation, reduction, hydrolysis, conjugation and the others toprovide a compound according to the present invention, are also includedwithin the claimed scope of the present invention.

The “salt” includes a salt of an inorganic acid, a salt of an organicacid, a salt of an inorganic base, a salt of an organic base and a saltof an acidic or basic amino acid, among them, a pharmacologicallyacceptable salt is preferable.

The preferable salt of an inorganic acid includes, for example, a saltof hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid andphosphoric acid. The preferable salt of an organic acid includes, forexample, a salt of acetic acid, succinic acid, fumaric acid, maleicacid, tartaric acid, citric acid, lactic acid, stearic acid, benzoicacid, methanesulfonic acid, ethanesulfonic acid, and p-toluenesulfonicacid.

The preferable salt of an inorganic base includes, for example, analkali metal salt such as sodium salt and potassium salt, an alkaliearth metal salt such as calcium salt and magnesium salt, aluminum salt,and ammonium salt. The preferable salt of an organic base includes, forexample, a salt of diethylamine, diethanolamine, meglumine, andN,N-dibenzylethylenediamine.

The preferable salt of an acidic amino acid includes, for example, asalt of aspartic acid and glutamic acid. The preferable salt of a basicamino acid includes, for example, a salt of arginine, lysine andornithine.

The “halogen” represents fluorine, chlorine, bromine or iodine.

The “C₁₋₆ alkyl” represents an alkyl of straight or branched chainhaving a carbon number of 1 to 6, and includes, for specific example,methyl, ethyl, 1-propyl (n-propyl), 2-propyl (i-propyl),2-methyl-1-propyl (i-butyl), 2-methyl-2-propyl (t-butyl), 1-butyl(n-butyl), 2-butyl (s-butyl), 1-pentyl, 2-pentyl, 3-pentyl,2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-2-butyl, 3-methyl-2-butyl,2,2-dimethyl-1-propyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-1-pentyl,3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl,3-methyl-2-pentyl, 4-methyl-2-pentyl, 2-methyl-3-pentyl,3-methyl-3-pentyl, 2,3-dimethyl-1-butyl, 3,3-dimethyl-1-butyl,2,2-dimethyl-1-butyl, 2-ethyl-1-butyl, 3,3-dimethyl-2-butyl, and2,3-dimethyl-2-butyl.

The “C₂₋₆ alkenyl” represents an alkenyl of straight or branched chainhaving one double bond and a carbon number of 2 to 6, and includes, forspecific example, ethenyl (vinyl), 1-propenyl, 2-propenyl (allyl),1-butenyl, 2-butenyl, 3-butenyl, pentenyl, and hexenyl.

The “C₃₋₆ alkenyl” represents an alkenyl of straight or branched chainhaving one double bond and a carbon number of 3 to 6, and includes, forspecific example, 2-propenyl (allyl), 2-butenyl, 3-butenyl, pentenyl,and hexenyl.

The “C₂₋₆ alkynyl” represents an alkynyl of straight or branched chainhaving one triple bond and a carbon number of 2 to 6, and includes, forspecific example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl,3-butynyl, pentynyl, and hexynyl.

The “C₃₋₆ alkynyl” represents an alkynyl of straight or branched chainhaving one triple bond and a carbon number of 3 to 6, and includes, forspecific example, 2-propynyl, 2-butynyl, 3-butynyl, pentynyl, andhexynyl.

The “C₁₋₆ alkylene” represents a divalent group derived by eliminatingfurther any one hydrogen from the “C₁₋₆ alkyl” defined above, andincludes, for specific example, methylene, 1,2-ethylene, 1,1-ethylene,1,3-propylene, tetramethylene, pentamethylene, and hexamethylene.

The “C₃₋₁₀ cycloalkyl” represents a mono- or di-cyclic saturatedaliphatic hydrocarbon group having a carbon number of 3 to 10, andincludes, for specific example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl,bicyclo[2.1.0]pentyl, bicyclo[3.1.0]hexyl, bicyclo[2.1.1]hexyl,bicyclo[4.1.0]heptyl, bicyclo[2.2.1]heptyl (norbornyl),bicyclo[3.3.0]octyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl,bicyclo[4.3.0]nonyl, bicyclo[3.3.1]nonyl, bicyclo[4.4.0]decyl (decalyl),and bicyclo[3.3.2]decyl.

The “C₆₋₁₀ aryl” represents an aromatic hydrocarbon ring group having acarbon number of 6 to 10, and includes, for specific example, phenyl,1-naphthyl, 2-naphthyl, indenyl, azulenyl, and heptalenyl.

The “heteroatom” represents nitrogen, oxygen, or sulfur.

The “5- to 10-membered heteroaryl” represents an aromatic ring grouphaving 5 to 10 atoms forming the ring and containing 1 to 5 heteroatoms,and includes, for specific example, furyl, thienyl, pyrrolyl,imidazolyl, triazolyl, tetrazolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, isothiazolyl, furazanyl, thiadiazolyl, oxadiazolyl, pyridyl,pyrazinyl, pyridazinyl, pyrimidinyl, triazinyl, purinyl, pteridinyl,quinolyl, isoquinolyl, naphthylidinyl, quinoxalinyl, cinnolinyl,quinazolinyl, phthalazinyl, imidazopyridyl, imidazothiazolyl,imidazoxazolyl, benzothiazolyl, benzoxazolyl, benzimidazolyl, indolyl,isoindolyl, indazolyl, pyrrolopyridyl, thienopyridyl, furopyridyl,benzothiadiazolyl, benzoxadiazolyl, pyridopyrimidinyl, benzofuryl,benzothienyl, and thienofuryl.

The preferable example of the “5- to 10-membered heteroaryl” includesfuryl, thienyl, pyrrolyl, imidazolyl, thiazolyl, pyrazolyl, oxazolyl,isoxazolyl, isothiazolyl, pyridyl, and pyrimidinyl.

The “3- to 10-membered non-aromatic heterocyclic group” represents

-   (1) a monocyclic or a bicyclic non-aromatic heterocyclic group-   (2) having 3 to 10 atoms in the ring,-   (3) containing 1 to 2 heteroatoms among the atoms of the ring,-   (4) optionally containing 1 to 2 double bonds in the ring,-   (5) optionally containing 1 to 3 carbonyl, sulfinyl, or sulfonyl in    the ring.

If the group contains nitrogen in the ring, the nitrogen may have a bondnot participating in the formation of the ring. The group includes, forspecific example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl,azepanyl, azocanyl, piperazinyl, diazepanyl, diazocanyl,diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, oxiranyl, oxetanyl, tetrahydrofuryl,tetrahydropyranyl, dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl,oxazolidinyl, and thiazolidinyl.

The preferable example of the “3- to 10-membered non-aromaticheterocyclic group” includes aziridinyl, azetidinyl, pyrrolidinyl,piperidinyl, azepanyl, piperazinyl, diazepanyl, morpholinyl,thiomorpholinyl, 1,1-dioxothiomorpholinyl, tetrahydrofuryl, andtetrahydropyranyl.

The “4- to 10-membered non-aromatic heterocyclic group” represents

-   (1) a monocyclic or a bicyclic non-aromatic heterocyclic group-   (2) having 4 to 10 atoms in the ring,-   (3) containing 1 to 2 heteroatoms among the atoms of the ring,-   (4) optionally containing 1 to 2 double bonds in the ring,-   (5) optionally containing 1 to 3 carbonyl, sulfinyl, or sulfonyl in    the ring.

If the group contains nitrogen in the ring, the nitrogen may have a bondnot participating in the formation of the ring. The group includes, forspecific example, azetidinyl, pyrrolidinyl, piperidinyl, azepanyl,azocanyl, piperazinyl, diazepanyl, diazocanyl,diazabicyclo[2.2.1]heptyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, oxetanyl, tetrahydrofuryl, tetrahydropyranyl,dioxanyl, tetrahydrothienyl, tetrahydrothiopyranyl, oxazolidinyl, andthiazolidinyl.

The preferable example of the “4- to 10-membered non-aromaticheterocyclic group” includes azetidinyl, pyrrolidinyl, piperidinyl,azepanyl, piperazinyl, diazepanyl, morpholinyl, thiomorpholinyl,1,1-dioxothiomorpholinyl, tetrahydrofuryl, and tetrahydropyranyl.

The “C₃₋₁₀ cycloalkyl-C₁₋₆ alkyl” represents a group obtained bysubstituting any one hydrogen of the above defined “C₁₋₆ alkyl” with theabove defined “C₃₋₁₀ cycloalkyl”, and includes, for specific example,cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl,cyclohexylmethyl, cycloheptylmethyl, cyclooctylmethyl, cyclononylmethyl,cyclodecylmethyl, bicyclo[2.2.1]heptylmethyl (norbornylmethyl), andbicyclo[4.4.0]decylmethyl (decarylmethyl).

The “C₆₋₁₀ aryl-C₁₋₆ alkyl” represents a group obtained by substitutingany one hydrogen of the above defined “C₁₋₆ alkyl” with the abovedefined “C₆₋₁₀ aryl”, and includes, for specific example, benzyl,1-naphthylmethyl, 2-naphthylmethyl, phenethyl, 1-naphthylethyl, and2-naphthylethyl.

The “5- to 10-membered heteroaryl-C₁₋₆ alkyl” represents a groupobtained by substituting any one hydrogen of the above defined “C₁₋₆alkyl” with the above defined “5- to 10-membered heteroaryl”, andincludes, for specific example, furylmethyl, thienylmethyl,pyrrolylmethyl, imidazolylmethyl, triazolylmethyl, tetrazolylmethyl,thiazolylmethyl, pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl,isothiazolylmethyl, furazanylmethyl, thiadiazolylmethyl,oxadiazolylmethyl, pyridylmethyl, pyrazinylmethyl, pyridazinylmethyl,pyrimidinylmethyl, triazinylmethyl, furylethyl, thienylethyl,pyrrolylethyl, imidazolylethyl, triazolylethyl, tetrazolylethyl,thiazolylethyl, pyrazolylethyl, oxazolylethyl, isoxazolylethyl,isothiazolylethyl, furazanylethyl, thiadiazolylethyl, oxadiazolylethyl,pyridylethyl, pyrazinylethyl, pyridazinylethyl, pyrimidinylethyl, andtriazinylethyl.

The preferable example of the “5- to 10-membered heteroaryl C₁₋₆ alkyl”includes furylmethyl, thienylmethyl, pyrrolylmethyl, imidazolylmethyl,thiazolylmethyl, pyrazolylmethyl, oxazolylmethyl, isoxazolylmethyl,isothiazolylmethyl, pyridylmethyl, pyrimidinylmethyl, furylethyl,thienylethyl, pyrrolylethyl, imidazolylethyl, thiazolylethyl,pyrazolylethyl, oxazolylethyl, isoxazolylethyl, isothiazolylethyl,pyridylethyl, and pyrimidinylethyl.

The “3- to 10-membered non-aromatic heterocyclic-C₁₋₆ alkyl” representsa group obtained by substituting any one hydrogen of the above defined“C₁₋₆ alkyl” with the above defined “3- to 10-membered heterocyclicgroup”, and includes, for specific example, aziridinylmethyl,azetidinylmethyl, pyrrolidinylmethyl, piperidinylmethyl, azepanylmethyl,azocanylmethyl, piperazinylmethyl, diazepanylmethyl, diazocanylmethyl,morpholinylmethyl, thiomorpholinylmethyl,1,1-dioxothiomorpholinylmethyl, oxiranylmethyl, oxetanylmethyl,tetrahydrofurylmethyl, tetrahydropyranylmethyl, dioxanylmethyl,tetrahydrothienylmethyl, tetrahydrothiopyranylmethyl,oxazolidinylmethyl, thiazolidinylmethyl, aziridinylethyl,azetidinylethyl, pyrrolidinylethyl, piperidinylethyl, azepanylethyl,azocanylethyl, piperazinylethyl, diazepanylethyl, diazocanylethyl,morpholinylethyl, thiomorpholinylethyl, 1,1-dioxothiomorpholinylethyl,oxiranylethyl, oxetanylethyl, tetrahydrofurylethyl,tetrahydropyranylethyl, dioxanylethyl, tetrahydrothienylethyl,tetrahydrothiopyranylethyl, oxazolidinylethyl, and thiazolidinylethyl.

The preferable example of the “3- to 10-membered non-aromaticheterocyclic-C₁₋₆ alkyl” includes azetidinylmethyl, pyrrolidinylmethyl,piperidinylmethyl, azepanylmethyl, piperazinylmethyl, diazepanylmethyl,morpholinylmethyl, thiomorpholinylmethyl, tetrahydrofurylmethyl,azetidinylethyl, pyrrolidinylethyl, piperidinylethyl, azepanylethyl,piperazinylethyl, diazepanylethyl, morpholinylethyl,thiomorpholinylethyl, and tetrahydrofuryl ethyl.

The “C₁₋₆ alkoxy” represents a group obtained by adding oxygen to theterminal of the above defined “C₁₋₆ alkyl”, and includes, for specificexample, methoxy, ethoxy, 1-propoxy (n-propoxy), 2-propoxy (i-propoxy),2-methyl-1-propoxy (i-butoxy), 2-methyl-2-propoxy (t-butoxy), 1-butoxy(n-butoxy), 2-butoxy (s-butoxy), 1-pentyloxy, 2-pentyloxy, 3-pentyloxy,2-methyl-1-butoxy, 3-methyl-1-butoxy, 2-methyl-2-butoxy,3-methyl-2-butoxy, 2,2-dimethyl-1-propoxy, 1-hexyloxy, 2-hexyloxy,3-hexyloxy, 2-methyl-1-pentyloxy, 3-methyl-1-pentyloxy,4-methyl-1-pentyloxy, 2-methyl-2-pentyloxy, 3-methyl-2-pentyloxy,4-methyl-2-pentyloxy, 2-methyl-3-pentyloxy, 3-methyl-3-pentyloxy,2,3-dimethyl-1-butoxy, 3,3-dimethyl-1-butoxy, 2,2-dimethyl-1-butoxy,2-ethyl-1-butoxy, 3,3-dimethyl-2-butoxy, and 2,3-dimethyl-2-butoxy.

The “C₁₋₆ alkylthio” represents a group obtained by adding sulfur to theterminal of the above defined “C₁₋₆ alkyl”, and includes, for specificexample, methylthio, ethylthio, 1-propylthio (n-propylthio),2-propylthio (i-propylthio), 2-methyl-1-propylthio (i-butylthio),2-methyl-2-propylthio (t-butylthio), 1-butylthio (n-butylthio),2-butylthio (s-butylthio), 1-pentylthio, 2-pentylthio, 3-pentylthio,2-methyl-1-butylthio, 3-methyl-1-butylthio, 2-methyl-2-butylthio,3-methyl-2-butylthio, 2,2-dimethyl-1-propylthio, 1-hexylthio,2-hexylthio, 3-hexylthio, 2-methyl-1-pentylthio, 3-methyl-1-pentylthio,4-methyl-1-pentylthio, 2-methyl-2-pentylthio, 3-methyl-2-pentylthio,4-methyl-2-pentylthio, 2-methyl-3-pentylthio, 3-methyl-3-pentylthio,2,3-dimethyl-1-butylthio, 3,3-dimethyl-1-butylthio,2,2-dimethyl-1-butylthio, 2-ethyl-1-butylthio, 3,3-dimethyl-2-butylthio,and 2,3-dimethyl-2-butylthio.

The “C₃₋₆ alkenyloxy” represents a group obtained by adding oxygen tothe terminal of the above defined “C₃₋₆ alkenyl”, and includes, forspecific example, 2-propenyloxy (allyloxy), 2-butenyloxy, 3-butenyloxy,pentenyloxy, and hexenyloxy.

The “C₃₋₆ alkenylthio” represents a group obtained by adding sulfur tothe terminal of the above defined “C₃₋₆ alkenyl”, and includes, forspecific example, 2-propenylthio (allylthio), 2-butenylthio,3-butenylthio, pentenylthio, and hexenylthio.

The “C₃₋₆ alkynyloxy” represents a group obtained by adding oxygen tothe terminal of the above defined “C₃₋₆ alkynyl”, and includes, forspecific example, 2-propynyloxy, 2-butynyloxy, 3-butynyloxy,pentynyloxy, and hexynyloxy.

The “C₃₋₆ alkynylthio” represents a group obtained by adding sulfur tothe terminal of the above defined “C₃₋₆ alkynyl”, and includes, forspecific example, 2-propynylthio, 2-butynylthio, 3-butynylthio,pentynylthio, and hexynylthio.

The “C₃₋₁₀ cycloalkoxy” represents a group obtained by adding oxygen tothe terminal of the above defined “C₃₋₁₀ cycloalkyl”, and includes, forspecific example, cyclopropoxy, cyclobutoxy, cyclopentyloxy,cyclohexyloxy, cycloheptyloxy, and cyclooctyloxy.

The “C₃₋₁₀ cycloalkylthio” represents a group obtained by adding sulfurto the terminal of the above defined “C₃₋₁₀ cycloalkyl”, and includes,for specific example, cyclopropylthio, cyclobutylthio, cyclopentylthio,cyclohexylthio, cycloheptylthio, and cyclooctylthio.

The “C₆₋₁₀ aryloxy” represents a group obtained by adding oxygen to theterminal of the above defined “C₆₋₁₀ aryl”, and includes, for specificexample, phenoxy, 1-naphthoxy, 2-naphthoxy, indenyloxy, azulenyloxy, andheptalenyloxy.

The “C₆₋₁₀ arylthio” represents a group obtained by adding sulfur to theterminal of the above defined “C₆₋₁₀ aryl”, and includes, for specificexample, phenylthio, 1-naphthylthio, 2-naphthylthio, indenylthio,azulenylthio, and heptalenylthio.

The “5- to 10-membered heteroaryloxy” represents a group obtained byadding oxygen to the terminal of the above defined “5- to 10-memberedheteroaryl”, and includes, for specific example, furyloxy, thienyloxy,pyrrolyloxy, imidazolyloxy, triazolyloxy, thiazolyloxy, pyrazolyloxy,oxazolyloxy, isoxazolyloxy, isothiazolyloxy, furazanyloxy,thiadiazolyloxy, oxadiazolyloxy, pyridyloxy, pyrazinyloxy,pyridazinyloxy, pyrimidinyloxy, and triazinyloxy.

The “5- to 10-membered heteroarylthio” represents a group obtained byadding sulfur to the terminal of the above defined “5- to 10-memberedheteroaryl”, and includes, for specific example, furylthio, thienylthio,pyrrolylthio, imidazolylthio, triazolylthio, thiazolylthio,pyrazolylthio, oxazolylthio, isoxazolylthio, isothiazolylthio,furazanylthio, thiadiazolylthio, oxadiazolylthio, pyridylthio,pyrazinylthio, pyridazinylthio, pyrimidinylthio, and triazinylthio.

The “4- to 10-membered non-aromatic heterocyclicoxy group” represents agroup obtained by adding oxygen to the terminal of the above defined “4-to 10-membered non-aromatic heterocyclic group”, and includes, forspecific example, azetidinyloxy, pyrrolidinyloxy, piperidinyloxy,azepanyloxy, azocanyloxy, piperazinyloxy, diazepanyloxy, diazocanyloxy,morpholinyloxy, thiomorpholinyloxy, 1,1-dioxothiomorpholinyloxy,oxetanyloxy, tetrahydrofuryloxy, tetrahydropyranyloxy,tetrahydrothienyloxy, and tetrahydrothiopyranyloxy.

The “4- to 10-membered non-aromatic heterocyclicthio group” represents agroup obtained by adding sulfur to the terminal of the above defined “4-to 10-membered non-aromatic heterocyclic group”, and includes, forspecific example, azetidinylthio, pyrrolidinylthio, piperidinylthio,azepanylthio, azocanylthio, piperazinylthio, diazepanylthio,diazocanylthio, oxetanylthio, tetrahydrofurylthio,tetrahydropyranylthio, tetrahydrothienylthio, andtetrahydrothiopyranylthio.

The “mono-C₁₋₆ alkylamino” represents a group obtained by substitutingone hydrogen of amino with the above defined “C₁₋₆ alkyl”, and includes,for specific example, methylamino, ethylamino, 1-propylamino(n-propylamino), 2-propylamino (i-propylamino), 2-methyl-1-propylamino(i-butylamino), 2-methyl-2-propylamino (t-butylamino), 1-butylamino(n-butylamino), 2-butylamino (s-butylamino), 1-pentylamino,2-pentylamino, 3-pentylamino, 2-methyl-1-butylamino,3-methyl-1-butylamino, 2-methyl-2-butylamino, 3-methyl-2-butylamino,2,2-dimethyl-1-propylamino, 1-hexylamino, 2-hexylamino, 3-hexylamino,2-methyl-1-pentylamino, 3-methyl-1-pentylamino, 4-methyl-1-pentylamino,2-methyl-2-pentylamino, 3-methyl-2-pentylamino, 4-methyl-2-pentylamino,2-methyl-3-pentylamino, 3-methyl-3-pentylamino,2,3-dimethyl-1-butylamino, 3,3-dimethyl-1-butylamino,2,2-dimethyl-1-butylamino, 2-ethyl-1-butylamino,3,3-dimethyl-2-butylamino, and 2,3-dimethyl-2-butylamino.

The “mono-C₃₋₁₀ cycloalkylamino” represents a group obtained bysubstituting one hydrogen of amino with the above defined “C₃₋₁₀cycloalkyl”, and includes, for specific example, cyclopropylamino,cyclobutylamino, cyclopentylamino, cyclohexylamino, cycloheptylamino,and cyclooctylamino.

The “mono-C₆₋₁₀ arylamino” represents a group obtained by substitutingone hydrogen of amino with the above defined “C₆₋₁₀ aryl”, and includes,for specific example, phenylamino, 1-naphthylamino, 2-naphthylamino,indenylamino, azulenylamino, and heptalenylamino.

The “mono-5- to 10-membered heteroarylamino” represents a group obtainedby substituting one hydrogen of amino with the above defined “5- to10-membered heteroaryl”, and includes, for specific example, furylamino,thienylamino, pyrrolylamino, imidazolylamino, triazolylamino,tetrazolylamino, thiazolylamino, pyrazolylamino, oxazolylamino,isoxazolylamino, isothiazolylamino, furazanylamino, thiadiazolylamino,oxadiazolylamino, pyridylamino, pyrazinylamino, pyridazinylamino,pyrimidinylamino, and triazinylamino.

The preferable example of the “mono-5- to 10-membered heteroarylamino”includes furylamino, thienylamino, pyrrolylamino, imidazolylamino,thiazolylamino, pyrazolylamino, oxazolylamino, isoxazolylamino,isothiazolylamino, pyridylamino, and pyrimidinylamino.

The “mono-4- to 10-membered non-aromatic heterocyclic amino” representsa group obtained by substituting one hydrogen of amino with the abovedefined “4- to 10-membered non-aromatic heterocyclic group”, andincludes, for specific example, azetidinylamino, pyrrolidinylamino,piperidinylamino, azepanylamino, azocanylamino, piperazinylamino,diazepanylamino, diazocanylamino, morpholinylamino,thiomorpholinylamino, 1,1-dioxothiomorpholinylamino, oxetanylamino,tetrahydrofurylamino, tetrahydropyranylamino, tetrahydrothienylamino,and tetrahydrothiopyranylamino.

The preferable example of the “mono-4- to 10-membered non-aromaticheterocyclic amino” includes pyrrolidinylamino, piperidinylamino,azepanylamino, piperazinylamino, diazepanylamino, morpholinylamino,thiomorpholinylamino, and tetrahydrofurylamino.

The “di-C₁₋₆ alkylamino” represents a group obtained by substituting twohydrogen of amino with the same or different groups of the above defined“C₁₋₆ alkyl”, and includes, for specific example, N,N-dimethylamino,N,N-diethylamino, N,N-di-n-propylamino, N,N-di-i-propylamino,N,N-di-n-butylamino, N,N-di-i-butylamino, N,N-di-s-butylamino,N,N-di-t-butylamino, N-ethyl-N-methylamino, N-n-propyl-N-methylamino,N-i-propyl-N-methylamino, N-n-butyl-N-methylamino,N-i-butyl-N-methylamino, N-s-butyl-N-methylamino, andN-t-butyl-N-methylamino.

Each of the substituents in the compound of the present inventionrepresented by the above formula (I) will be described below.

(Meaning of R¹)

R¹ represents a 3- to 10-membered non-aromatic heterocyclic groupwherein the group is limited to a group having nitrogen as a ringconstituent atom and the nitrogen having a bonding hand, or a grouprepresented by the formula —NR^(11a)R^(11b), wherein R^(11a) and R^(11b)may be the same or different and each represents hydrogen, C₁₋₆ alkyl,C₃₋₆ alkenyl, C₃₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl or a 4- to 10-membered non-aromatic heterocyclicgroup, and R^(11a) and R^(11b) may be substituted with a substituentselected from Substituent Group A or Substituent Group B.

R¹ may be substituted with a substituent selected from Substituent GroupA or Substituent Group B.

The preferable example of R¹ includes a group represented by the formula(II):

wherein a represents an integer of 1 to 4;a group represented by the formula (III):

wherein b represents an integer of 1 to 3, and Z represents oxygen,sulfur, carbonyl, sulfonyl, or a group represented by the formula—NR^(Z)—, wherein R^(Z) represents hydrogen or C₁₋₆ alkyl, and thegroups represented by the formula (II) or (III) may be substituted witha substituent selected from Substituent Group A or Substituent Group B;ora group represented by the formula —NR^(11c)R^(11d), wherein R^(11c)represents hydrogen or C₁₋₆ alkyl, and R^(11d) represents C₁₋₆ alkyl ora group represented by the formula (IV):

wherein c represents an integer of 1 to 3, and Z¹ represents oxygen,sulfur, carbonyl, sulfonyl or a group represented by the formula—NR^(Z1)—, wherein R^(Z1) represents hydrogen or C₁₋₆ alkyl, and R^(11d)d may be substituted with a substituent selected from Substituent GroupA or Substituent Group B.

The more preferable example of R¹ includes azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, azepan-1-yl, piperazin-1-yl,diazepan-1-yl, morpholin-4-yl, thiomorpholin-4-yl,1,1-dioxothiomorpholin-4-yl, or a group represented by the formula—NR^(11e)R^(11f), wherein R^(11e) represents hydrogen or C₁₋₆ alkyl,R^(11f) represents C₁₋₆ alkyl, pyrrolidin-3-yl, piperidin-3-yl,piperidin-4-yl or tetrahydropyran-4-yl, and R^(11f) may be substitutedwith a substituent selected from Substituent Group D, and each of theabove substituents may be substituted with a substituent selected fromSubstituent Group D.

The even more preferable example of R¹ includes azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl, piperazin-1-yl, diazepan-1-yl,morpholin-4-yl, and each of the above substituents may be substitutedwith a substituent selected from Substituent Group E, or a grouprepresented by the formula —NR^(11g)R^(11h), wherein R^(11g) representshydrogen or methyl, R^(11h) represents n-propyl, n-butyl,pyrrolidin-3-yl, piperidin-3-yl, piperidin-4-yl or tetrahydropyran-4-yl,and R^(11h) may be substituted with a substituent selected fromSubstituent Group F.

The especially preferable example of R¹ includes azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl, wherein azetidin-1-ylmay be substituted with a substituent selected from Substituent Group Gand pyrrolidin-1-yl, piperidin-1-yl and piperazin-1-yl are substitutedwith a substituent selected from Substituent Group G, or a grouprepresented by the formula —N(CH₃)R^(11i) wherein R^(11i) representsn-propyl, n-butyl, pyrrolidin-3-yl or piperidin-4-yl, and R^(11i) issubstituted with a substituent selected from Substituent Group H.

The most preferable example of R¹ includes azetidin-1-yl,pyrrolidin-1-yl, piperidin-1-yl or piperazin-1-yl, wherein azetidin-1-ylmay be substituted with a substituent selected from Substituent GroupG-1 and pyrrolidin-1-yl, piperidin-1-yl and piperazin-1-yl aresubstituted with a substituent selected from Substituent Group G-1, orazetidin-1-yl having dimethylamino, pyrrolidin-1-yl having dimethylaminoor piperidin-1-yl having dimethylamino, a group represented by theformula —N(CH₃)R^(11j) wherein R^(11j) represents 1-methylpiperidin-4-ylor 1-ethylpiperidin-4-yl, azetidin-1-yl optionally substituted with asubstituent selected from Substituent Group G-2, pyrrolidin-1-ylsubstituted with a substituent selected from Substituent Group G-2,piperidin-1-yl substituted with a substituent selected from SubstituentGroup G-2 or a group represented by the formula —N(CH₃)R^(11k), whereinR^(11k) represents 3-(dimethylamino)propyl or1-[2-(dimethylamino)ethyl]piperidin-4-yl.

The most preferable example of R¹ also includes[2-(dimethylamino)ethyl]piperazin-1-yl, 4-pyrrolidin-1-ylpiperidin-1-yl,4-[(dimethylamino)methyl]piperidin-1-yl, 4-azetidin-1-ylpiperidin-1-yl,4-[3-(dimethylamino)azetidin-1-yl]piperidin-1-yl,4-(4-methylpiperazin-1-yl)piperidin-1-yl,4-(1-methylpiperidin-4-yl)piperazin-1-yl,4-(1-methylazetidin-3-yl)piperazin-1-yl,4-(dimethylamino)piperidin-1-yl, 4-(azetidin-1-ylmethyl)piperidin-1-yl,4-(pyrrolidin-1-ylmethyl)piperidin-1-yl,(3S)-3-(dimethylamino)pyrrolidin-1-yl,(3R)-3-(dimethylamino)pyrrolidin-1-yl, azetidin-1-yl, pyrrolidin-1-yl,morpholin-4-yl, 4-methylpiperazin-1-yl, 3-hydroxyazetidin-1-yl,1,3′-biazetidin-1′-yl, 3-(hydroxymethyl)azetidin-1-yl,3-(dimethylamino)azetidin-1-yl, 3-[(dimethylamino)methyl]azetidin-1-yl,4-hydroxypiperidin-1-yl, 4-(hydroxymethyl)piperidin-1-yl,(3R)-3-hydroxypyrrolidin-1-yl, (3S)-3-hydroxypyrrolidin-1-yl,3-(azetidin-1-ylmethyl)azetidin-1-yl,3-(2-dimethylaminoacetoxy)azetidin-1-yl,methyl(1-methylpiperidin-4-yl)amino,(1-ethylpiperidin-4-yl)(methyl)amino,[3-(dimethylamino)propyl](methyl)amino or{1-[2-(dimethylamino)ethyl]piperidin-4-yl} (methyl)amino.

(Meaning of Substituent Group A)

The Substituent Group A represents a group consisting of halogen,hydroxyl, mercapto, nitro, cyano and oxo.

(Meaning of Substituent Group B)

The Substituent Group B represents a group consisting of C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, a 3- to 10-membered non-aromatic heterocyclicgroup, C₁₋₆ alkoxy, C₃₋₆ alkenyloxy, C₃₋₆ alkynyloxy, C₃₋₁₀ cycloalkoxy,C₆₋₁₀ aryloxy, 5- to 10-membered heteroaryloxy, 4- to 10-memberednon-aromatic heterocyclicoxy, C₁₋₆ alkylthio, C₃₋₆ alkenylthio, C₃₋₆alkynylthio, C₃₋₁₀ cycloalkylthio, C₆₋₁₀ arylthio, 5- to 10-memberedheteroarylthio, 4- to 10-membered non-aromatic heterocyclicthio and agroup represented by the formula -T¹-T²-T³, wherein T¹ represents adirect bond or C₁₋₆ alkylene, T² represents carbonyl, sulfinyl,sulfonyl, a group represented by the formula —C(═O)—O—, a grouprepresented by the formula —O—C(═O)—, a group represented by the formula—SO₂—O—, a group represented by the formula —O—SO₂—, a group representedby the formula —NR^(T1)—, a group represented by the formula—C(═O)—NR^(T1)—, a group represented by the formula —NR^(T1)—C(═O)—, agroup represented by the formula —SO₂—NR^(T1)— or a group represented bythe formula —NR^(T1)—SO₂—, T³ represents hydrogen, C₁₋₆ alkyl, C₃₋₆alkenyl, C₃₋₆ alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl or a 4- to 10-membered non-aromatic heterocyclic group, andR^(T1) represents hydrogen or C₁₋₆ alkyl.

Each group included in Substituent Group B may be substituted with asubstituent selected from Substituent Group C.

(Meaning of Substituent Group C)

The Substituent Group C represents a group consisting of halogen,hydroxyl, mercapto, nitro, cyano, oxo, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₁₀ cycloalkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, a3- to 10-membered non-aromatic heterocyclic group, C₁₋₆ alkoxy, C₁₋₆alkylthio, mono-C₁₋₆ alkylamino and di-C₁₋₆ alkylamino.

(Meaning of Substituent Group D)

The Substituent Group D represents a group consisting of halogen,hydroxyl, mercapto, cyano, formyl, oxo, C₁₋₆ alkyl, C₃₋₁₀-cycloalkyl,C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆ alkylamino,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, diazepanyl and agroup represented by -T⁴-T⁵, wherein T⁴ represents carbonyl or sulfonyl,and T⁵ represents C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, azetidinyl,pyrrolidinyl, piperidinyl, hydroxyl, C₁₋₆ alkoxy, amino, mono-C₁₋₆alkylamino or di-C₁₋₆ alkylamino.

Each group included in Substituent Group D may be substituted withhydroxyl, C₁₋₆ alkyl, di-C₁₋₆ alkylamino, azetidinyl or pyrrolidinyl.

(Meaning of Substituent Group E)

The Substituent Group E represents a group consisting of methyl, ethyl,dimethylamino, azetidinyl, pyrrolidinyl, piperidinyl and piperazinyl.

Each group included in Substituent Group E may be substituted withhydroxyl, methyl, dimethylamino, azetidinyl, pyrrolidinyl or piperidinyl

(Meaning of Substituent Group F)

The Substituent Group F represents a group consisting of methyl, ethyl,n-propyl, acetyl, dimethylamino, diethylamino, azetidinyl, pyrrolidinyland piperazinyl.

Each group included in Substituent Group F may be substituted withmethyl or dimethylamino.

(Meaning of Substituent Group G)

The Substituent Group G represents a group consisting of dimethylamino,azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, dimethylaminomethyl,dimethylaminoethyl, azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl andpiperidin-1-ylmethyl.

Each group included in Substituent Group G may be substituted withmethyl or dimethylamino.

(Meaning of Substituent Group G-1)

The Substituent Group G-1 represents a group consisting of azetidinyl,pyrrolidinyl, piperidinyl, piperazinyl, dimethylaminomethyl,dimethylaminoethyl, azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl andpiperidin-1-ylmethyl.

Each group included in Substituent Group G-1 may be substituted withmethyl or dimethylamino.

(Meaning of Substituent Group G-2)

The Substituent Group G-2 represents a group consisting of hydroxyl,methoxy, hydroxymethyl and dimethylaminoacetoxy.

(Meaning of Substituent Group H)

The Substituent Group H represents a group consisting of dimethylamino,diethylamino, dimethylaminoethyl, dimethylaminopropyl and1-methylazetidin-3-yl.

(Meaning of R² and R³)

R² and R³ represent hydrogen.

(Meaning of R⁴, R⁵, R⁶ and R⁷)

R⁴, R⁵, R⁶ and R⁷ may be the same or different and each representshydrogen, halogen, hydroxyl, cyano, trifluoromethyl, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₁₋₆ alkoxy, amino, mono-C₁₋₆ alkylamino, di-C₁₋₆alkylamino or a group represented by the formula —CO—R¹², wherein R¹²represents hydrogen, hydroxyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, amino, mono-C₁₋₆alkylamino or di-C₁₋₆ alkylamino.

The preferable example of R⁴, R⁵, R⁶ and R⁷ includes hydrogen, halogen,C₁₋₆ alkyl, C₁₋₆ alkoxy and trifluoromethyl.

The more preferable example of R⁴, R⁵, R⁶ and R⁷ includes hydrogen,halogen and C₁₋₆ alkyl.

The even more preferable example of R⁴, R⁵, R⁶ and R⁷ includes hydrogen,fluorine, chlorine and methyl.

R⁴, R⁵, R⁶ and R⁷ may be in any one of the following cases: (1) all ofthem represent hydrogen, (2) all of them represent substituents otherthan hydrogen, and (3) some of them represent hydrogen and the othersrepresent substituents other than hydrogen. Preferably, 2 to 4 of R⁴,R⁵, R⁶ and R⁷ represent hydrogen.

Preferable example for a group represented by the formula:

includes groups represented by the formulas:

or a group represented by the formula:

(Meaning of R⁸)

R⁸ represents hydrogen or C₁₋₆ alkyl.

The preferable example of R⁸ includes hydrogen.

(Meaning of R⁹)

R⁹ represents a 3- to 10-membered non-aromatic heterocyclic groupwherein the group is limited to a group having nitrogen as a ringconstituent atom and the nitrogen having a bonding hand, or a grouprepresented by the formula —NR^(11a)R^(11b), wherein R^(11a) and R^(11b)represent the same meaning as described above.

R⁹ may be substituted with a substituent selected from Substituent GroupA or Substituent Group B.

The preferable example of R⁹ includes mono-C₁₋₆ alkylamino, mono-C₃₋₁₀cycloalkylamino, mono-C₆₋₁₀ arylamino, mono-5- to 10-memberedheteroarylamino or mono-4- to 10-membered non-aromatic heterocyclicamino, wherein R⁹ may be substituted with a substituent selected fromSubstituent Group A or Substituent Group B.

The more preferable example of R⁹ includes mono-C₃₋₁₀ cycloalkylamino ormono-C₆₋₁₀ arylamino, wherein R⁹ may be substituted with a substituentselected from Substituent Group A or Substituent Group B.

The even more preferable example of R⁹ includes mono-C₃₋₁₀cycloalkylamino or mono-C₆₋₁₀ arylamino, wherein R⁹ may be substitutedwith a substituent selected from Substituent Group I.

The Substituent Group I represents a group consisting of halogen,trifluoromethyl, cyano, C₁₋₆ alkyl and C₁₋₆ alkoxy.

The especially preferable example of R⁹ includes cyclopentylamino,cyclohexylamino, cycloheptylamino and phenylamino, wherein R⁹ may besubstituted with a substituent selected from Substituent Group I.

The most preferable example of R⁹ includes phenylamino optionallysubstituted with a substituent selected from the above Substituent GroupI.

(Meaning of n)

n represents an integer of 1 or 2.

The preferable example of n includes 1.

(Meaning of X)

X represents a group represented by the formula —C(R¹⁰)═ or nitrogen,wherein R¹⁰ represents hydrogen, halogen, cyano, C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl or a group represented by the formula —CO—R¹²,wherein R¹² represents the same meaning as described above.

The preferable example of X includes a group represented by the formula—C(R^(10a))═ or nitrogen, wherein R^(10a) represents hydrogen, halogenor cyano.

The more preferable example of X includes a group represented by theformula —CH═ or nitrogen.

The preferable compound of the formula (I) includes a compound obtainedby selecting respective aspects of R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, Xand n in the compound and combining them arbitrarily.

The preferable compound of the formula (I) includes, other than thecompounds described in Examples, the compounds illustrated below; butthe present invention is not limited to the compounds described inExamples and the compounds illustrated below.

-   (1)    N-(4-{[2-({[(1-ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (2)    N-(4-{[2-({[(1-ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (3)    N-{2-fluoro-4-[(2-{[(4-methyl-1,4-diazepan-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (4)    N-(4-fluorophenyl)-N′-{2-fluoro-4-[(2-{[(3-pyrrolidin-1-ylazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide,-   (5)    N-{2-fluoro-4-[(2-{[(4-methylpiperazin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (6)    N-[4-({2-[({4-[2-(dimethylamino)ethyl]-1,4-diazepan-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-phenylcyclopropane-1,1-dicarboxamide,-   (7)    N-(4-{[2-({[3-(dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (8)    N-(4-{[2-({[3-(dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (9)    N-(4-{[2-({[3-(dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (10)    N-[2-fluoro-4-({2-[({methyl[1-(1-methylazetidin-3-yl)piperidin-4-yl]amino}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-phenylcyclopropane-1,1-dicarboxamide,-   (11)    N-(2-fluoro-4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (12)    N-(4-fluorophenyl)-N′-(4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide,-   (13)    N-(2-fluoro-4-{[2-({[(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (14)    N-{2-fluoro-4-[(2-{[(4-hydroxy-1,4′-bipiperidin-1′-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-phenylcyclopropane-1,1-dicarboxamide,-   (15)    N-(4-{[2-({[{1-[3-(dimethylamino)propyl]piperidin-4-yl}(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (16)    N-(4-{[2-({[(3-azetidin-1-ylpropyl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (17)    N-(2-fluoro-4-{[2-({[methyl(3-pyrrolidin-1-ylpropyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (18)    N-(4-{[2-({[[3-(dimethylamino)propyl](methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (19)    N-(2-fluoro-4-{[2-({[methyl(4-pyrrolidin-1-ylbutyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (20)    N-[2-fluoro-4-({2-[(morpholin-4-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (21)    N-[4-({2-[(azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (22)    N-(2-fluoro-4-{[2-({[methyl(3-morpholin-4-ylpropyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (23)    N-[2-fluoro-4-({2-[({methyl[3-(4-methylpiperazin-1-yl)propyl]amino}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (24)    N-(4-fluorophenyl)-N′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide,-   (25)    N-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-2-thienylcyclopropane-1,1-dicarboxamide,-   (26)    N-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-1,3-thiazol-2-ylcyclopropane-1,1-dicarboxamide,-   (27)    N-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(5-methylisoxazol-3-yl)cyclopropane-1,1-dicarboxamide,-   (28)    N-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(3-methylisoxazol-5-yl)cyclopropane-1,1-dicarboxamide,-   (29)    N-{2-fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (30)    N-{2-fluoro-4-[(2-{[(4-methoxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (31)    N-{2-fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (32)    N-{2-fluoro-4-[(2-{[(3-methoxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (33)    N-(2-fluoro-4-{[2-({[(2-methoxyethyl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (34)    N-(2-fluoro-4-{[2-({[4-(3-hydroxyazetidin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (35)    N-(2-fluoro-4-{[2-({[methyl(tetrahydro-2H-pyran-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (36)    N-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-3-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (37)    N-[4-({2-[({3-[(dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (38)    N-[4-({2-[({3-[(dimethylamino)methyl]pyrrolidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (39)    N-(2-fluoro-4-{[2-({[methyl(1-methylpyrrolidin-3-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (40)    N-{2-fluoro-4-[(2-{[(3-hydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (41)    N-{2-fluoro-4-[(2-{[(3-methoxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (42)    N-{4-[(2-{[(3,4-dihydroxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (43)    N-{2-fluoro-4-[(2-{[(3-hydroxy-4-methoxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (44)    N-{4-[(2-{[(3,4-dimethoxypyrrolidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (45)    N-{2-fluoro-4-[(2-{[(3-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (46)    N-{2-fluoro-4-[(2-{[(3-methoxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (47)    N-(4-{[2-({[3-(dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

The more preferable compound of the formula (I) includes the compoundsillustrated below;

-   (1)    N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (2)    N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (3)    N-(4-Fluorophenyl)-N′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide,-   (4)    N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (5)    N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (6)    N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (7)    N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (8)    N-(2-Fluoro-4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (9)    N-(2-Fluoro-4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (10)    N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (11)    N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (12)    N-(4-Fluorophenyl)-N′-(2-fluoro-4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide,-   (13)    N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (14)    N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (15)    N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (16)    N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (17)    N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-phenylcyclopropane-1,1-dicarboxamide,-   (18)    N-(4-{[2-({[(1-Ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,-   (19)    N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (20)    N-(4-Fluorophenyl)-N′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide,-   (21)    N-{2-Fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (22)    N-[4-({2-[(1,3′-Biazetidin-1′-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (23)    N-(2-Fluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (24)    N-(4-{[2-({[3-(Dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (25)    N-[4-({2-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (26)    N-{2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (27)    N-(2-Fluoro-4-{[2-({[4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (28)    N-(2-Fluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (29)    N-(2-Fluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (30)    N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (31)    N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (32)    N-(2,5-Difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (33)    N-[2,5-Difluoro-4-({2-[({3-[(dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (34)    N-(2,5-Difluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (35)    N-{4-[(2-{[3-(Azetidin-1-ylmethyl)azetidin-1-ylcarbonyl]amino}pyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (36)    N-(2,5-Difluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (37)    N-{2,5-Difluoro-4-[(4-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyrimidin-6-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (38) N-[4-({4-[({3-[(Dimethylamino)methyl]azetidin    1-yl}carbonyl)amino]pyrimidin-6-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (39)    N-(2,5-Difluoro-4-{[4-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (40)    N-(2,5-Difluoro-4-{[4-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (41)    N-(2,5-Difluoro-4-{[4-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (42)    N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (43)    N-{2,5-Difluoro-4-[(2-{[(4-methylpiperazin-1-yl)carbonyl]amino}pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (44)    N-{2,5-Difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (45)    N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]oxy}-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (46)    N-(2,5-Difluoro-4-{[2-({[3-(2-dimethylaminoacetoxy)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (47)    N-(2,5-Difluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,-   (48)    N-(2,5-Difluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.

The phrase “may be substituted with a substituent selected fromSubstituent Group” or “optionally substituted with a substituentselected from Substituent Group” means “may be substituted with 1 to 3substituents selected arbitrarily from the substituents described in theSubstituent Group.”

(General Production Method)

The compound of the present invention can be produced by methodsdescribed below. But the method for producing the compound of thepresent invention is not limited to these methods.

[Production Method 1] a Method for Producing Intermediates (1m) and (1n)

[Production Method 1-a] a Method for Producing Intermediates (1m) and(1n) Via Coupling of a Derivative of 2-Aminopyridine or6-Aminopyrimidine with Phenol

In the scheme, L¹ represents a leaving group; R¹⁰¹ represents C₁₋₆ alkylor benzyl; R¹⁰² represents C₁₋₆ alkyl, benzyl or2-(trimethylsilyl)ethyl; R⁸⁰ represents C₁₋₆ alkyl; P represents aprotecting group for amino; and the other symbols represent the samemeaning as defined above.

The compound (1a) includes, for example, 4-nitropicolinic acid ester,4-chloropicolinic acid ester, 6-chloropyrimidine-4-carboxylic acidester. 4-nitropicolinic acid ester and 4-chloropicolinic acid ester canbe obtained by the esterification of 4-nitropicolinic acid and4-chloropicolinic acid, both of which are commercially available. Among6-chloropyrimidine-4-carboxylic acid ester, methyl6-chloropyrimidine-4-carboxylate is described in Ukr. Kihm. Zh., 1982,Vol. 48, p 67 (CAS No. 6627-22-1). 6-chloropyrimidine-4-carboxylic acidester also can be produced according to a method described in J.Heterocycl. Chem., 1, 130 (1964).

The compound (1d) includes, for example, commercially availablecompounds such as 2-amino-4-chloropyridine and4-amino-6-chloropyrimidine. The compound (1d) also can be produced via<Process 1A-1>, <Process 1A-2> and <Process 1A-3> described below, usingthe compound (1a) as a starting material.

The compound (1f) includes, for example, commercially availablecompounds such as p-methylaminophenol sulfate.

The compound (1e) can be obtained by protecting a group represented bythe formula R⁸⁰NH— of the compound (1f). The general reaction forprotecting amino can be used. For example, the compound (1e) can beobtained by a reaction of the compound (1f) with ethyl chloroformate,methyl chloroformate, benzyl chloroformate, di-t-butyl dicarbonate ortrifluoroacetic anhydride.

The compound (1g) includes, for example, commercially availablecompounds such as 4-acetoamidophenol, N-(4-hydroxyphenyl)formamide,4-(N-t-butoxycarbonylamino)phenol and 4-trifluoroacetoamidophenol.

The compound (1h) includes, for example, commercially availablecompounds such as 4-nitrophenol, 2-chloro-4-nitrophenol,2-fluoro-4-nitrophenol, 3-fluoro-4-nitrophenol and3-methyl-4-nitrophenol.

The compound (1i) includes, for example, commercially availablecompounds such as 4-aminophenol, 4-amino-3-chlorophenol hydrochloride,4-amino-2,5-dimethylphenol, 4-amino-2,6-dichlorophenol and5-amino-2-hydroxybenzonitrile.

The above compounds can also be produced from commercially availablecompounds by a known method.

<Process 1A-1>

The process is a process for producing the compound (1b) from thecompound (1a). For example, hydrolysis using a base can be used. As thebase, an inorganic base such as sodium hydroxide, potassium hydroxideand lithium hydroxide can be used. As the solvent, methanol, ethanol,water or the like can be used. The reaction temperature is between 0° C.and a reflux temperature. The reaction time is between 10 minutes and 30hours.

<Process 1A-2>

The process is a process for rearrangement of the compound (1b) to thecompound (1c). The compound (1c) can be obtained by a reaction of thecompound (1b) with an alcohol represented by the formula R¹⁰²—OH in thepresence of diphenylphosphoryl azide and triethylamine. The preferableexample of R¹⁰² includes t-butyl, benzyl and 2-(trimethylsilyl)ethyl. Asthe solvent, N,N-dimethylformamide, N-methylpyrrolidone, toluene or thelike can be used as well as t-butanol or benzylalcohol. The reactiontemperature is between room temperature and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

<Process 1A-3>

The process is a process for producing the compound (1d) from thecompound (1c) by deprotection of carbamate. For the reaction, generaldeprotection for amino can be used and specific examples aredeprotection using an acid such as hydrochloric acid and trifluoroaceticacid, deprotection using an inorganic base such as sodium hydroxide andpotassium hydroxide, and deprotection using tetrabutylammonium fluoride.As the solvent, methanol, ethanol, water, tetrahydrofuran,N,N-dimethylformamide or the like can be used. The reaction temperatureis between room temperature and a reflux temperature. The reaction timeis between 10 minutes and 30 hours.

<Process 1A-4> <Process 1A-6> <Process 1A-7> <Process 1A-9> <Process1A-10>

These processes are processes for coupling the compound (1d) with thecompounds (1e), (1f), (1g), (1h) or (1i) to produce the compounds (1j),(1n), (1k), (1l) or (1m), respectively. As the solvent,N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide,2-ethoxyethanol, chlorobenzene or the like can be used. A base or anacid may be added in the reaction system, and specifically an organicbase such as triethylamine and diisopropylethylamine, an inorganic basesuch as potassium carbonate, cesium carbonate and sodium hydride, or anacid such as pyridine hydrochloride and hydrochloric acid can be used.The reaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 30 hours.

<Process 1A-5>

The process is a process for deprotecting the compound (1j) to producethe compound (1n). For the reaction, general deprotection for amino canbe applied, for specific example, deprotection using an acid such ashydrochloric acid and trifluoroacetic acid, deprotection using aninorganic base such as sodium hydroxide and potassium hydroxide, anddeprotection using tetrabutylammonium fluoride. When a protecting groupis benzyloxycarbonyl and R⁴, R⁵, R⁶, R⁷ and R¹⁰ are not any of chlorine,bromine and iodine, deprotection by catalytic hydrogenation usingpalladium-carbon or palladium hydroxide as a catalyst can also be used.As the solvent, methanol, ethanol, water, tetrahydrofuran,N,N-dimethylformamide or the like can be used. The reaction temperatureis between room temperature and a reflux temperature. The reaction timeis between 10 minutes and 30 hours.

<Process 1 A-8>

The process is a process for deprotecting the compound (1k) to producethe compound (1m). The conditions similar to those in <Process 1A-5> canbe used.

<Process 1A-11>

The process is a process for reducing nitro of the compound (1l) toproduce the compound (1m). Generally used conditions for reduction fromnitro to amino can be applied, for specific example, reduction usingiron-ammonium chloride, or iron-acetic acid. When R⁴, R⁵, R⁶, R⁷ and R¹⁰are not any of chlorine, bromine and iodine, catalytic hydrogenationusing palladium hydroxide or palladium-carbon as a catalyst also can beused. As the solvent, methanol, ethanol, water, N,N-dimethylformamide,ethyl acetate, tetrahydrofuran or the like can be used. The reactiontemperature is between room temperature and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

<Process 1A-12>

The process is a process for alkylating the compound (1m) to produce thecompound (1n). Reductive amination of aldehyde or ketone can converthydrogen to C₁₋₆ alkyl. As the reducing agent, sodium cyanoborohydrideand sodium triacetoxyborohydride can be used. As the solvent, methanol,tetrahydrofuran, dichloromethane, dichloroethane or the like can beused.

A method for reducing a benzotriazole derivative with sodium borohydridecan also be used, as described in Tetrahedron, 47(16), 2683 (1991).Specifically for example, the compound (1n) wherein R⁸⁰ is methyl can beobtained by reduction with sodium borohydride, abenzotriazol-1-ylmethylaniline derivative obtained by a reaction of thecompound (1 m) with 1-(hydroxymethyl)-1H-benzotriazole. In the processfor producing a benzotriazol-1-ylmethylaniline derivative, an alcoholsuch as methanol or ethanol, or a mixed solvent of an alcohol withN,N-dimethylformamide, acetic acid or water can be used for the solvent.The reaction temperature is between −5° C. and a reflux temperature. Thereaction time is between 10 minutes and 30 hours. In the process ofreduction with sodium borohydride, tetrahydrofuran, dioxane, an alcoholsuch as methanol or ethanol, or a mixed solvent of an alcohol withN,N-dimethylformamide or the like can be used as the solvent. Thereaction temperature is between −5° C. and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

<Process 1A-13>

The process is an alternative method for producing the compound (1j) byalkylating the compound (1k) to produce the compound (1j). The compound(1j) can be obtained by a reaction with alkyl halide in the presence ofa base such as potassium carbonate or sodium hydride. As the solvent,tetrahydrofuran, N,N-dimethylformamide or the like can be used. Thereaction temperature is between 0° C. and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

[Production Method 1-B] a Method for Producing an Intermediate (1x) ViaCoupling of Pyridine-2-Carboxylic Acid Ester or Pyrimidine-6-CarboxylicAcid Ester with a Derivative of Phenol

In the scheme, the symbols represent the same meaning as defined above.

<Process 1B-1> <Process 1B-2> <Process 1B-3> <Process 1B-4> <Process1B-5>

These processes are processes for coupling the compound (1a) with thecompound (1f), (1g), (1e), (1i) or (1 h) to produce the compound (1o),(1p), (1s), (1r) or (1q), respectively. The methods similar to those in<Process 1A-4> can be used.

<Process 1B-6>

The process is a process for protecting amino of the compound (1o) toproduce the compound (1s). A general reaction for protecting amino canbe used. Specifically for example, a reaction with ethyl chloroformate,methyl chloroformate, benzyl chloroformate, di-t-butyl dicarbonate andtrifluoroacetic anhydride can be used. A base may be added in thereaction system, and an organic base such as pyridine, triethylamine anddiisopropylethylamine, and an inorganic base such as sodium carbonate,potassium carbonate and sodium hydrogencarbonate can be used. As thesolvent, tetrahydrofuran, acetone, water, dioxane or the like can beused. The reaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 30 hours.

<Process 1B-7>

The process is a process for alkylating the compound (1p) to produce thecompound (1s). The methods similar to those in <Process 1A-13> can beused.

<Process 1B-8>

The process is a process for alkylating the compound (1r) to produce thecompound (1o). The methods similar to those in <Process 1A-12> can beused.

<Process 1B-9>

The process is a process for protecting amino of the compound (1r) toproduce the compound (1p). The methods similar to those in <Process1B-6> can be used.

<Process 1B-10>

The process is a process for reducing nitro of the compound (1q) toproduce the compound (1r). The methods similar to those in <Process1A-11> can be used.

<Process 1B-11>

The process is a process for producing the compound (1t) from thecompound (1ps) (the compound (1ps) represents the compound (1p) and thecompound (1s) described in [Production method 1-B]). The methods similarto those in <Process 1A-1> can be used.

<Process 1B-12>

The process is a process for producing the compound (1u) from thecompound (1t). The methods similar to those in <Process 1A-2> can beused.

<Process 1B-13>

The process is a process for deprotecting the two protecting groups“R¹⁰²—O—C(═O)—” and “P” of the compound (1u) to produce the compound(1x). Depending on the kind of the protecting groups, deprotection usingan acid such as hydrochloric acid and trifluoroacetic acid, deprotectionusing an inorganic base such as sodium hydroxide and potassiumhydroxide, deprotection using tetrabutylammonium fluoride, anddeprotection by catalytic hydrogenation using palladium-carbon orpalladium hydroxide as a catalyst can be appropriately combined toproduce the compound (1x).

<Production 1B-14> <Production 1B-16>

These processes are processes for deprotecting only one of the twoprotecting groups “R¹⁰²—O—C(═O)—” and “P” of the compound (1u) toproduce the compound (1v) or the compound (1w), respectively. Theprocess is applicable only when the two protecting groups“R¹⁰²—O—C(═O)—” and “P” are different. Specifically, for example, when agroup represented by the formula R¹⁰²—O—C(═O)— is2-(trimethylsilyl)ethoxycarbonyl and P is benzyloxycarbonyl,deprotection using tetrabutylammonium fluoride or deprotection bycatalytic hydrogenation can be applied to deprotect selectively only oneof the two protecting groups.

<Process 1B-15>

The process is a process for deprotecting the compound (1v) to producethe compound (1x). The method described in <Process 1A-5> can be used.

<Process 1B-17>

The process is a process for deprotecting the compound (1w) to producethe compound (1x). The method described in <Process 1A-5> can be used.

[Production method 2] An alternative production method of intermediates(1l), (1m), (1k), (1j) and (1n) from a pyridine or pyrimidine derivative(2a) having leaving groups L¹ at the 4-position and L² at the 2-positionor 6-position

In the scheme, L² represents a leaving group. The other symbolsrepresent the same meanings as defined above.

The compound (2a) includes, for example, commercially availablecompounds such as 4,6-dichloropyrimidine, 2-chloro-4-nitropyridine, and2,4-dichloropyridine. The compound (2a) also can be produced fromcommercially available compounds by a known method.

<Process 2-1> <Process 2-2> <Process 2-3> <Process 2-4> <Process 2-5>

These processes are processes for coupling the compound (2a) with thecompound (1h), (1i), (1g), (1e) or (1f) to produce the compound (2b),(2c), (2d), (2e) or (2f), respectively. Preferably, in (2a), L¹ is areactive group having higher reactivity than L². In a specificcombination, for example, L¹ is nitro and L² is chlorine. The methodssimilar to those in <Process 1A-4> can be used for these processes.

<Process 2-6>

The process is a process for reducing nitro of the compound (2b) toproduce the compound (2c). Generally used conditions of reduction fromnitro to amino can be used. Specifically, for example a reduction usingiron-ammonium chloride or iron-acetic acid can be used. As the solvent,methanol, ethanol, water, N,N-dimethylformamide, tetrahydrofuran or thelike can be used. The reaction temperature is between room temperatureand a reflux temperature. The reaction time is between 10 minutes and 30hours.

<Process 2-7>

The process is a process for protecting amino of the compound (2c) toproduce the compound (2d). The methods similar to those in <Process1B-6> can be used.

<Process 2-8>

The process is a process for alkylating the compound (2d) to produce thecompound (2e). The methods similar to those in <Process 1A-13> can beused.

<Process 2-9>

The process is a process for protecting amino of the compound (2f) toproduce the compound (2e). The methods similar to those in <Process1B-6> can be used.

<Process 2-10>

The process is a process for alkylating the compound (2c) to produce thecompound (2f). The methods similar to those in <Process 1A-12> can beused.

<Process 2-11> <Process 2-12> <Process 2-13> <Process 2-14> <Process2-15>

These process are processes for converting the leaving group L² of thecompound (2b), (2c), (2d), (2e) or (2f) to amino to produce the compound(1l), (1m), (1k), (1j) or (1n), respectively. The process can be carriedout using, for example, an ammonia-ethanol solution in a sealed tube.The reaction temperature is a reflux temperature. The reaction time isbetween 10 minutes and 100 hours.

[Production Method 3] a Method for Producing an Intermediate Representedby the Formula (XI)

In the formula, R^(9a) represents a 3- to 10-membered non-aromaticheterocyclic group wherein the group is limited to a group havingnitrogen as a ring constituent atom and the nitrogen having a bondinghand, or a group represented by the formula —NR^(11a)R^(11b), whereinR^(11a) and R^(11b) represent the same meaning as described above.R^(9a) may be substituted with a substituent selected from SubstituentGroup A or Substituent Group B. Where R^(9a) has hydroxyl, primary aminoor secondary amino as a substituent group, the group may be protected bya suitable protecting group. The other symbols represent the samemeanings as defined above.

In the formula, R¹⁰³ represents C₁₋₆ alkyl or benzyl. The other symbolsrepresent the same meanings as defined above.

The compound (3a) includes, for example,1-ethoxycarbonylcyclopropanecarboxylic acid,1-methoxycarbonylcyclopropanecarboxylic acid,1-benzyloxycarbonylcyclobutanecarboxylic acid and1-ethoxycarbonylcyclobutanecarboxylic acid.

The compound (3b) includes, for example,1-chlorocarbonylcyclopropanecarboxylic acid ethyl ester and1-chlorocarbonylcyclobutanecarboxylic acid ethyl ester.

The above compounds can also be produced from commercially availablecompounds by a known method.

<Process 3-1>

The process is a process for condensing the compound (3a) with an aminerepresented by the formula R^(9a)—H or a salt thereof to produce thecompound (3c). For the process, a general condensation of a carboxylicacid with an amine can be used. For specific example, as the solvent,N,N-dimethylformamide and tetrahydrofuran can be used, and for thecondensing agent, carbonyldiimidazole, dicyclohexylcarbodiimide,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride, and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate can be used. An organic base such as triethylaminealso can be appropriately used. The reaction temperature is between 0°C. and a reflux temperature. The reaction time is between 10 minutes and30 hours.

<Process 3-2>

The process is a process for condensing the compound (3b) with an aminerepresented by the formula R^(9a)—H or a salt thereof to produce thecompound (3c). As the solvent, N,N-dimethylformamide, tetrahydrofuran,dichloromethane or the like can be used. An organic base such astriethylamine also can be appropriately used. The reaction temperatureis between 0° C. and a reflux temperature. The reaction time is between10 minutes and 30 hours.

<Process 3-3>

The process is a process for producing the compound (3d) from thecompound (3c). For the process, hydrolysis using a base can be used. Forthe base, lithium hydroxide or the like can be used. If R¹⁰³ is benzyland R^(9a) does not have chlorine, bromine and iodine as a substituentgroup, catalytic hydrogenation using palladium-carbon or palladiumhydroxide as a catalyst also can be used. As the solvent, methanol,ethanol, water, N,N-dimethylformamide, tetrahydrofuran, ethyl acetate orthe like can be used. The reaction temperature is between 0° C. and areflux temperature. The reaction time is between 10 minutes and 30hours.

<Process 3-4>

The process is a process for condensing the compound (1mn) (the compound(1mn) represents the compounds (1m) and (1n) described in [Productionmethod 1-A]) with the compound (3d) to produce the compound (XI). Forthe condensing agent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride,(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate or the like can be used. An organic base such astriethylamine also can be appropriately used. As the solvent,tetrahydrofuran, N,N-dimethylformamide or the like can be used. Thereaction temperature is between 0° C. and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

<Process 3-5> <Process 3-6> <Process 3-10>

These processes are processes for producing the compounds (3e), (3f) or(3h) from the compound (1w), (1or) (the compound (1or) represents thecompounds (1o) and (1r) described in [Production method 1-B], the sameapplies hereinafter), or (2f), respectively. The methods similar tothose in <Process 3-4> can be used.

<Process 3-7>

The process is a process for producing the compound (3g) from thecompound (3f). The methods similar to those in <Process 1A-1> can beused.

<Process 3-8>

The process is a process for rearrangement of the compound (3g) to thecompound (3e). The methods similar to those in <Process 1A-2> can beused.

<Process 3-9>

The process is a process for deprotecting the compound (3e) to producethe compound (XI). The methods similar to those in <Process 1A-5> can beused.

<Process 3-11>

The process is a process for converting the leaving group L² of thecompound (3h) to amino to produce the compound (XI). The methods similarto those in <Process 2-11> can be used.

[Production Method 4] an Alternative Method for Synthesizing VariousIntermediates in [Production Method 3]

In the scheme, the symbols represent the same meanings as defined above.

<Process 4-1> <Process 4-4> <Process 4-7> <Process 4-10>

These processes are processes for condensing the compound (1mn), (1w),(1or) or (2f) with the compound (3a) to produce the compound (4a), (4c),(4e) or (4g), respectively. The method similar to those in <Process 3-4>can be used.

<Process 4-2> <Process 4-5> <Process 4-8> <Process 4-11>

These processes are processes for producing the compound (4b), (4d),(4f) or (4h) from the compound (4a), (4c), (4e) or (4g), respectively.The methods similar to those in <Process 1A-1> can be used. But in<Process 4-5> and <Process 4-8> deprotection is carried out under such acondition that the protecting group of amino or carboxyl at 2-positionof pyridine or 4-position of pyrimidine may not be deprotected.Specifically, for example, if R¹⁰¹ or R¹⁰² is C₁₋₆ alkyl or2-(trimethylsilyl)ethyl and R¹⁰³ is benzyl, then catalytic hydrogenationcan be carried out to produce the compound (4d) or (4f).

<Process 4-3> <Process 4-6> <Process 4-9> <Process 4-12>

These processes are processes for condensing the compound (4b), (4d),(4f) or (4h) with an amine represented by the formula R^(9a)—H or a saltthereof to produce the compound (XI), (3e), (3f) or (3h), respectively.The method similar to those in <Process 3-1> can be used.

[Production Method 5] an Alternative Method (2) for Synthesizing VariousIntermediates in [Production Method 3]

In the scheme, the symbols represent the same meanings as defined above.

<Process 5-1>

The process is a process for condensing the compound (3d) with thecompound (1fi) (the compound (1fi) represents the compounds (1f) and(1i) described in [Production method 1-A]) to produce the compound (5a).The method similar to those in <Process 3-4> can be used.

<Process 5-2> <Process 5-3> <Process 5-4> <Process 5-5>

These processes are processes for coupling the compound (1a), (1c), (1d)or (2a) with the compound (5a) to produce the compound (3f), (3e), (XI)or (3h), respectively. The methods similar to those in <Process 1A-4>can be used.

[Production Method 6] a Method for Producing an Intermediate Representedby the Formula (XII)

In the formula, R^(1a) represents a 3- to 10-membered non-aromaticheterocyclic group wherein the group is limited to a group havingnitrogen as a ring constituent atom and the nitrogen having a bondinghand, or a group represented by the formula —NR^(11a)R^(11b), whereinR^(11a) and R^(11b) represent the same meaning as described above.R^(1a) may be substituted with a substituent selected from SubstituentGroup A or Substituent Group B. Where R^(1a) has hydroxyl, primary aminoor secondary amino as a substituent group, the group may be protected bya suitable protecting group. The other symbols represent the samemeanings as defined above.

In the scheme, the symbols represent the same meanings as defined above.

<Process 6-1> <Process 6-2> <Process 6-3> <Process 6-4> <Process 6-5>

These processes are processes for producing the compound (6a), (6b),(6c), (6d) or (6e) from the compound (1l), (1m), (1k), (1j) or (1n),respectively. For example, a method wherein the compound (1l), (1m),(1k), (1j) or (1n) is converted to a carbamic acid ester derivativeusing a compound represented by the formula Ar—OC(═O)—Cl, wherein Arrepresents a phenyl group optionally substituted with one or twosubstituent(s) selected from halogen, methyl, methoxy and nitro,followed by reacting with an amine can be used.

Alternatively, the compound (1l), (1m), (1k), (1j) or (1n) can bereacted with a carbamate derivative, an isocyanate derivative to convertto a corresponding urea derivative. As the solvent, chloroform, toluene,N-methylpyrrolidone, N,N-dimethylformamide, dimethylsulfoxide,chlorobenzene or the like can be used. A mixed solvent of the abovesolvent and water also can be used. A base also can be used.Specifically, an organic base such as pyridine, triethylamine anddiisopropylethylamine, and an inorganic base such as potassiumcarbonate, cesium carbonate, sodium hydride and sodium hydroxide can beused. The reaction temperature is between 0° C. and a refluxtemperature. The reaction time is between 10 minutes and 30 hours.

After the process, in order to convert substituent groups on R^(1a),generally used reactions such as oxidation, reduction, esterification,amidation, introduction of protecting groups, deprotection andhydrolysis can also be carried out in a suitable succeeding process.Specifically, for example, the method includes a method wherein thecompound (1l), (1k) or (1j) is reacted with a ketone oraldehyde-containing amine, followed by reductive amination with an amineto introduce an amine side chain on R^(1a). As the reducing agent,sodium cyanoborohydride and sodium triacetoxyborohydride or the like canbe used. As the solvent, methanol, tetrahydrofuran, dichloromethane,dichloroethane or the like can be used. Furthermore, the compound (1l),(1k) or (1j) can be reacted with an ester-containing amine to produce acompound, an ester portion of which is then hydrolyzed with a base suchas lithium hydroxide, sodium hydroxide and potassium hydroxide inhydrous ethanol, followed by converting with a condensing agent to anamide derivative. As the solvent, N,N-dimethylformamide, tetrahydrofuranor the like can be used. As the condensing agent,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate can be used. The reaction temperature is between 0°C. and a reflux temperature. The reaction time is between 10 minutes and30 hours.

<Process 6-6>

The process is a process for reducing the compound (6a) to produce thecompound (6b). The methods similar to those in <Process 1A-11> can beused.

<Process 6-7>

The process is a process for protecting amino of the compound (6b) toproduce the compound (6c). The methods similar to those in <Process1B-6> can be used.

<Process 6-8>

The process is a process for alkylating the compound (6c) to produce thecompound (6d). The methods similar to those in <Process 1A-13> can beused.

<Process 6-9>

The process is a process for deprotecting the compound (6d) to producethe compound (6e). The methods similar to those in <Process 1A-5> can beused.

<Process 6-10>

The process is a process for alkylating the compound (6b) to produce thecompound (6e). The methods similar to those in <Process 1A-12> can beused.

[Production Method 7] a Method for Producing the Compound of the PresentInvention Represented by the Formula (I)

In the formula, the symbols represent the same meanings as definedabove.

In the scheme, the symbols represent the same meanings as defined above.

<Process 7-1>

The process is a process for producing the compound (1) of the presentinvention from the compound (7a), that is, the above intermediate (XI).

-   (1) When R^(1a) or R^(9a) does not contain hydroxyl, primary amino    or secondary amino:    Using a compound represented by the formula Ar—OC(═O)—Cl, wherein Ar    represents the same meaning as defined above, the compound (7a) can    be converted to a carbamic acid ester derivative, which is then    reacted with an amine to produce the compound (1) of the present    invention. Alternatively, the compound (7a) can be reacted with a    carbamate derivative, an isocyanate derivative to convert to the    compound (1) of the present invention. As the solvent, chloroform,    toluene, N-methylpyrrolidone, N,N-dimethylformamide, dimethyl    sulfoxide, chlorobenzene or the like can be used. A mixed solvent of    the above solvent and water also can be used. A base also can be    used, and specifically, an organic base such as pyridine,    triethylamine and diisopropylethylamine, and an inorganic base such    as potassium carbonate, cesium carbonate, sodium hydride and sodium    hydroxide can be used. The reaction temperature is between 0° C. and    a reflux temperature. The reaction time is between 10 minutes and 30    hours.-   (2) When R^(1a) or R^(9a) contains hydroxyl, primary amino or    secondary amino:

After these substituents are suitably protected, the above reaction canbe carried out followed by deprotecting suitably to produce the compound(I) of the present invention.

(3) After the process, in order to convert substituent groups on R^(1a)or R^(9a), generally used reactions such as oxidation, reduction,esterification, amidation, protection, deprotection and hydrolysis canalso be carried out in a suitable succeeding process, as described in<Process 6-1> of the above [Production method 6].<Process 7-2>

The process is a process for producing the compound (I) of the presentinvention from the compound (7b), that is, the above intermediate (XII).

(1) When R^(1a) or R^(9a) does not contain hydroxyl, primary amino orsecondary amino:

(Method 1)

The compound (7b) can be condensed with the compound (3d) to produce thecompound (1) of the present invention. As a condensing agent,1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride,(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate or the like can be used. An organic base such astriethylamine also can be used. As the solvent, tetrahydrofuran,N,N-dimethylformamide or the like can be used. The reaction temperatureis between 0° C. and a reflux temperature. The reaction time is between10 minutes and 30 hours.

(Method 2) When R^(1a), R^(9a) or R¹⁰ does not contain alkoxycarbonyl:

The compound (7b) can be condensed with the compound (3a), R¹⁰³ of theresultant compound is then deprotected, followed by condensing with anamine or a salt thereof to produce the compound (I) of the presentinvention.

In condensation of the compound (7b) with the compound (3a), as thecondensing agent, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride,(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate or the like can be used. A base such astriethylamine can also be suitably used. As the solvent,tetrahydrofuran, N,N-dimethylformamide or the like can be used. Thereaction temperature is between 0° C. and a reflux temperature. Thereaction time is between 10 minutes and 30 hours.

For the deprotection of R¹⁰³, hydrolysis using a base or the like can beused.

In condensation with an amine or a salt thereof, general condensation ofa carboxylic acid with an amine can be used. Specifically for example,as the solvent, N,N-dimethylformamide and tetrahydrofuran can be used,and as the condensing agent, carbonyl diimidazole, dicyclohexylcarbodiimide, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride and(1H-1,2,3-benzotriazol-1-yloxy)(tri(dimethylamino))phosphoniumhexafluorophosphate can be used. A base such as triethylamine can alsobe suitably used. The reaction temperature is between 0° C. and a refluxtemperature. The reaction time is between 10 minutes and 30 hours.

-   (2) When R^(1a) or R^(9a) contains hydroxyl, primary amino or    secondary amino:

After the substituent is protected if necessary, the above reaction canbe carried out, followed by deprotecting suitably to produce thecompound (1) of the present invention.

-   (3) After the process, in order to convert substituent groups on    R^(1a) or R^(9a), generally used reactions such as oxidation,    reduction, esterification, amidation, protection, deprotection and    hydrolysis can also be carried out, as described in <Process 6-1> of    the above [Production method 6].    <Process 7-3>

The process is a process for producing the compound (7c) from thecompound (1d). The methods similar to those in <Process 6-1> can beused, for example, a method wherein the compound (1d) is converted to acarbamic acid ester derivative using a compound represented by theformula Ar—OC(═O)—Cl, wherein Ar represents the same meaning as definedabove, followed by reacting with an amine can be used. Alternatively,the compound (1d) can be reacted with a carbamate derivative, anisocyanate derivative to convert to a corresponding urea derivative. Asthe solvent, chloroform, toluene, N-methylpyrrolidone,N,N-dimethylformamide, dimethylsulfoxide, chlorobenzene or the like canbe used. A mixed solvent of the above solvent and water also can beused. A base also can be used. Specifically, an organic base such aspyridine, triethylamine and diisopropylethylamine, and an inorganic basesuch as potassium carbonate, cesium carbonate, sodium hydride and sodiumhydroxide can be used. The reaction temperature is between 0° C. and areflux temperature. The reaction time is between 10 minutes and 30hours.

<Process 7-4>

The process is a process for producing the compound (I) of the presentinvention from the compound (7c).

-   (1) When R^(1a) or R^(9a) does not contain hydroxyl, primary amino    or secondary amino:

The compound (I) of the present invention can be obtained by a couplingreaction of the compound (7c) and the compound (5a). The methods similarto those in <Process 1A-4> can be used. As the solvent,N-methylpyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide,2-ethoxyethanol, chlorobenzene or the like can be used. A base or anacid may be added in the reaction system, and specifically an organicbase such as triethylamine and diisopropylethylamine, an inorganic basesuch as potassium carbonate, cesium carbonate and sodium hydride, or anacid such as pyridine hydrochloride and hydrochloric acid can be used.The reaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 30 hours.

-   (2) When R^(1a) or R^(9a) contains hydroxyl, primary amino or    secondary amino:

After these substituents are suitably protected, the above reaction canbe carried out followed by deprotecting suitably to produce the compound(1) of the present invention.

-   (3) After the process, in order to convert substituent groups on    R^(1a) or R^(9a), generally used reactions such as oxidation,    reduction, esterification, amidation, protection, deprotection and    hydrolysis can also be carried out in a suitable succeeding process,    as described in <Process 6-1> of the above [Production method 6].

[Production Method 8] a Method for Producing an Intermediate (1d),Wherein X is a Group Represented by the Formula—

In the scheme, L³ represents chlorine or bromine; X¹⁰¹ representschlorine, bromine or iodine; R^(10b) represents halogen, cyano, C₁₋₆alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl or a group represented by the formula—CO—R¹², wherein R¹² represents the same meaning as defined above;R^(10d) represents C₁₋₆ alkyl; R^(10e) represents hydrogen or C₁₋₄alkyl; R^(10f), R^(10g) and R^(10h) may be the same or different andeach represents hydrogen or C₁₋₄ alkyl, with the proviso that the totalcarbon number of R^(10f), R^(10g) and R^(10h) is 0 or more to 4 or less;R^(10k) represents C₁₋₆ alkyl; and the other symbols represent the samemeanings as defined above.

<Process 8-1>

The process is a process for chlorinating, brominating or iodinating the5-position of the compound (8a) to produce the compound (8b). Forexample, a halogenating agent such as iodine, N-iodosuccinimide,bromine, N-bromosuccinimide and N-chlorosuccinimide can be used. As thesolvent, for example, N,N-dimethylformamide, dimethyl sulfoxide,dichloromethane and acetonitrile can be used. The reaction temperatureis between 0° C. and a reflux temperature. The reaction time is between10 minutes and 48 hours.

<Process 8-2>

The process is a process for converting X¹⁰¹ of the compound (8b) tocyano to produce the compound (8c). Concerning the combination of L³ andX¹⁰¹ upon cyanation, X¹⁰¹ is preferably iodine or bromine when L³ ischlorine, and X¹⁰¹ is preferably iodine when L³ is bromine. For example,in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) anddichlorobis(triphenylphosphine)palladium(II), 0.5-0.6 equivalent of zinccyanide is used relative to the compound (8b), or 1.0-1.2 equivalent ofpotassium cyanide or trimethylsilyl cyanide is used relative to thecompound (8b). As the solvent, for example, N,N-dimethylformamide,dioxane or tetrahydrofuran can be used. The reaction temperature isbetween room temperature and a reflux temperature. The reaction time isbetween 10 minutes and 10 hours.

<Process 8-3>

The process is a process for producing the compound (8d) from thecompound (8c). Hydrolysis using an inorganic base such as potassiumcarbonate and a hydrogen peroxide can be used. As the solvent, dimethylsulfoxide or the like can be used. The reaction temperature is between0° C. and a reflux temperature. The reaction time is between 10 minutesand 10 hours. A method of heating under reflux in a solvent such astoluene and tetrahydrofuran in the presence of potassiumtrimethylsilanolate, as described in Tetrahedron Lett., 41, 3747 (2000),also can be used. The reaction time is between 10 minutes and 60 hours.

<Process 8-4>

The process is a process for producing the compound (8e) from thecompound (8b). A method of reacting with (1-ethoxyvinyl)tributyltin inthe presence of a palladium catalyst such asdichlorobis(triphenylphosphine)palladium(II) andtetrakis(triphenylphosphine)palladium(0) can be used. In the reactionsystem, a salt such as lithium chloride may be added. As the solvent,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone or the likecan be used. The reaction temperature is between room temperature and areflux temperature. The reaction time is between 10 minutes and 60hours.

As for a document that complements the above method, Tetrahedron, 53(14), 5159 (1997) can be mentioned.

<Process 8-5>

The process is a process for producing the compound (8f) from thecompound (8b). A method of reacting an alcohol represented by theformula R^(10d)—OH with carbon monoxide in the presence of a palladiumcatalyst such as dichlorobis(triphenylphosphine)palladium(II) can beused. In the reaction system, a base such as triethylamine anddiisopropylethylamine may be added. As the solvent, an alcoholrepresented by the formula R^(10d)—OH, tetrahydrofuran,N,N-dimethylformamide, N-methylpyrrolidone, dimethyl sulfoxide or thelike can be used. The reaction temperature is between room temperatureand a reflux temperature. The reaction time is between 10 minutes and 60hours.

As for a document that complements the above method, Tetrahedron Lett.,25 (51), 5939 (1984) can be mentioned.

<Process 8-6>

The process is a process for producing the compound (8g) from thecompound (8b). The compound (8b) can be reacted with an acetylenederivative in the presence of a palladium catalyst such asdichlorobis(triphenylphosphine)palladium(II) to produce the compound(8g). In the reaction system, an organic base such as triethylamine oran inorganic base such as potassium carbonate and sodium hydroxide maybe added. A monovalent copper halide may coexist. As the solvent,tetrahydrofuran, N,N-dimethylformamide, N-methylpyrrolidone, dioxane,1.2-dimethoxyethane, toluene, benzene, acetonitrile or the like can beused. The reaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 60 hours.

<Process 8-7>

The process is a process for producing the compound (8h) from thecompound (8b). The compound (8b) can be reacted with a trialkylvinyltinderivative in the presence of a palladium catalyst such asdichlorobis(triphenylphosphine)palladium(II) to produce the compound(8h). In the reaction system, hexamethylphosphoramide or the like may beadded. As the solvent, tetrahydrofuran, N,N-dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide or the like can be used. Thereaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 60 hours.

As for a document that complements the above method, Tetrahedron, 53(14), 5159 (1997) can be mentioned.

<Process 8-8>

The process is a process for producing the compound (8k) from thecompound (8b). A method of reacting with carbon monoxide in the presenceof a palladium catalyst such asdichlorobis(triphenylphosphine)palladium(II), and sodium formate, asdescribed in Bull. Chem. Soc. Jpn., 67 (8), 2329 (1994), can be used. Asthe solvent, tetrahydrofuran, N,N-dimethylformamide,N-methylpyrrolidone, dimethyl sulfoxide or the like can be used. Thereaction temperature is between room temperature and a refluxtemperature. The reaction time is between 10 minutes and 60 hours.

<Process 8-9>

The process is a process for producing the compound (8m) from thecompound (8b). A method of reacting with a reagent prepared from alkylmagnesium halide and zinc(II) chloride in the presence of a palladiumcatalyst such as dichlorobis(triphenylphosphine)palladium(II), asdescribed in J. Org. Chem., 2001, 66 (20), 605, can be used. As thesolvent, tetrahydrofuran or the like can be used. The reactiontemperature is between room temperature and a reflux temperature. Thereaction time is between 10 minutes and 60 hours. Alternatively, amethod of reacting with tetraalkyltin in the presence of a palladiumcatalyst such as dichlorobis(triphenylphosphine)palladium(II), asdescribed in Tetrahedron Lett. 1996, 37 (14), 2409-2412, can be used. Asthe solvent, toluene or the like can be used. The reaction temperatureis between room temperature and a reflux temperature. The reaction timeis between 10 minutes and 60 hours.

The reactions similar to described in the processes of <Process 8-1> to<Process 8-9> can be applied to the conversion of the substituent at the5-position (R¹⁰) of the pyridine ring of various intermediates describedin [Production Method 1] to [Production Method 7].

The “leaving group” may be any group generally known as a leaving groupin organic synthesis, and is not particularly limited. Specifically forexample, it includes halogen such as chlorine, bromine and iodine;nitro; alkylsulfonyloxy such as methanesulfonyloxy,trifluoromethanesulfonyloxy and ethanesulfonyloxy; arylsulfonyloxy suchas benzenesulfonyloxy and p-toluenesulfonyloxy; and alkanoyloxy such asacetoxy and trifluoroacetoxy.

The amino-protecting group may be any group generally known as anamino-protecting group in organic synthesis, and is not particularlylimited. Specifically for example, it includes substituted orunsubstituted acyl such as formyl, acetyl, chloroacetyl, dichloroacetyl,propionyl, phenylacetyl, phenoxyacetyl and thienylacetyl; alkoxycarbonylsuch as t-butoxycarbonyl; substituted or unsubstituted benzyloxycarbonylsuch as benzyloxycarbonyl and 4-nitrobenzyloxycarbonyl; substituted orunsubstituted alkyl such as methyl, t-butyl and 2,2,2-trichloroethyl;substituted benzyl such as trityl, 4-methoxybenzyl, 4-nitrobenzyl anddiphenylmethyl; alkylcarbonyloxyalkyl such as pivaloyloxymethyl;alkylsilyl such as trimethylsilyl and t-butyldimethylsilyl; andalkylsilylalkoxyalkyl such as trimethylsilylmethoxymethyl,trimethylsilylethoxymethyl, t-butyldimethylsilylmethoxymethyl,t-butyldimethylsilylethoxymethyl.

These protecting groups can be deprotected by a conventional method suchas hydrolysis and reduction depending on the kind of the protectinggroup used.

The hydroxyl-protecting group may be any group generally known as ahydroxyl-protecting group in organic synthesis, and is not particularlylimited. Specifically for example, it includes alkylsilyl such astrimethylsilyl and t-butyldimethylsilyl; alkoxymethyl such asmethoxymethyl and 2-methoxyethoxymethyl; tetrahydropyranyl; substitutedor unsubstituted benzyl such as benzyl, 4-methoxybenzyl,2,4-dimethoxybenzyl, 2-nitrobenzyl, 4-nitrobenzyl and trityl; alkenylsuch as allyl; and acyl such as formyl and acetyl.

These protecting groups can be deprotected by a conventional method suchas hydrolysis and reduction depending on the kind of the protectinggroup used.

The carboxyl-protecting group may be any group generally known as acarboxyl-protecting group in organic synthesis, and is not particularlylimited. For example, it includes substituted or unsubstituted alkylsuch as methyl, ethyl, i-propyl, t-butyl, 2-iodoethyl and2,2,2-trichloroethyl; alkoxymethyl such as methoxymethyl, ethoxymethyland i-butoxymethyl; acyloxymethyl such as butylyloxymethyl andpivaloyloxymethyl; alkoxycarbonyloxyethyl such as1-methoxycarbonyloxyethyl and 1-ethoxycarbonyloxyethyl; and substitutedor unsubstituted benzyl such as benzyl, 4-methoxybenzyl, 2-nitrobenzyland 4-nitrobenzyl.

These protecting groups can be deprotected by a conventional method suchas hydrolysis and reduction depending on the kind of the protectinggroup used.

In addition to the above protecting groups, groups described in Greeneet al., “Protective Groups in Organic Synthesis”, 3rd Edition, JOHNWILEY & SONS, INC. can be used.

There have been described above the typical examples of a method forproducing the compound (I) according to the present invention. Each ofthe starting materials and various reagents may be a salt, a hydrate ora solvate, varies depending on a starting material, a solvent and thelike to be used, and is not limited to a particular one as long as itdoes not inhibit a reaction. A solvent to be used varies depending on astarting material, a reagent and the like, and is not limited to aparticular one as long as it does not inhibit a reaction and candissolve the starting material to some extent.

The compound (I) according to the present invention, if provided as afree form, can be converted to a form of a salt or a hydrate which theforgoing may form by a conventional method.

The compound (I) according to the present invention, if provided as theform of a salt or a hydrate of the compound (I), can be converted to afree form of the compound (I) by a conventional method.

The compound (I) according to the present invention and the variousisomers (such as geometric isomers and optical isomers) of the compound(I) according to the present invention can be purified and isolated by aconventional separation means, including recrystallization, diastereomersalt method, enzyme separation method, and various chromatographies suchas thin-layer chromatography, column chromatography and gaschromatography.

The compound (I) of the present invention is generally mixed with anappropriate additive and formulated to use as a medicament. But thecompound of the present invention may be used alone without anyadditive.

The above additives include excipients, binders, lubricants,disintegrators, coloring agents, taste correctives, emulsifiers,surfactants, dissolving aids, suspending agents, isotonizing agents,buffering agents, antiseptics, antioxidants, stabilizers, absorptionaccelerators and the like. These also may be appropriately combined touse if desired.

The excipients include, for example, lactose, white soft sugar, glucose,corn starch, mannitol, sorbitol, starch, pregelatinized starch, dextrin,crystalline cellulose, soft silicic anhydride, aluminum silicate,calcium silicate, magnesium aluminometasilicate and calciumhydrogenphosphate.

The binders include, for example, polyvinyl alcohol, methylcellulose,ethylcellulose, gum arabic, tragacanth, gelatin, shellac,hydroxypropylmethylcellulose, hydroxypropylcellulose,carboxymethylcellulose sodium, polyvinylpyrrolidone and macrogol. Thelubricants includes magnesium stearate, calcium stearate, sodium stearylfumarate, talc, polyethylene glycol and colloidal silica.

The disintegrators includes, for example, crystalline cellulose, agar,gelatin, calcium carbonate, sodium hydrogencarbonate, calcium citrate,dextrin, pectin, low-substituted hydroxypropylcellulose,carboxymethylcellulose, carboxymethylcellulose calcium, croscarmellosesodium, carboxymethyl starch and carboxymethyl starch sodium.

The coloring agents include, for example, those approved for addition topharmaceuticals, such as iron sesquioxide, yellow iron sesquioxide,carmine, caramel, β-carotene, titanium oxide, talc, riboflavin sodiumphosphate, yellow aluminum lake and the like.

The taste correctives include cocoa powder, menthol, aromatic powders,mentha oil, borneol, powdered cinnamon bark and the like.

The emulsifiers or surfactants include, for example, stearyltriethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid,lecitin, glycerin monostearate, sucrose fatty acid esters and glycerinfatty acid esters.

The dissolving aids include, for example, polyethylene glycol, propyleneglycol, benzyl benzoate, ethanol, cholesterol, triethanolamine, sodiumcarbonate, sodium citrate, polysorbate 80 and nicotinamide.

The suspending agents include, for example, hydrophilic polymers such aspolyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose andhydroxypropylcellulose, in addition to the above surfactants.

The isotonizing agents include, for example, glucose, sodium chloride,mannitol and sorbitol.

The buffering agents include, for example, buffer solutions ofphosphate, acetate, carbonate and citrate.

The antiseptics include, for example, methylparaben, propylparaben,chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid andsorbic acid.

The antioxidants include, for example, sulfite, ascorbic acid andα-tocopherol.

The stabilizers include those commonly used in pharmaceuticals.

The absorption accelerators include those commonly used inpharmaceuticals.

The formulation may be in an oral form such as tablets, powders,granules, capsules, syrups, lozenges and inhalants; an externalapplication form such as suppositories, ointment, eye salve, tape, eyedrops, nose drops, ear drops, pap and lotion; and an injection.

An oral formulation may be formulated by combining appropriately theabove additives, and may be coated on the surface if necessary.

An external application may be formulated by combining appropriately theabove additives, particularly excipients, binders, taste correctives,emulsifiers, surfactants, dissolving aids, suspending agents,isotonizing agents, antiseptics, antioxidants, stabilizers andabsorption accelerators.

An injection may be formulated by combining appropriately the aboveadditives, particularly emulsifiers, surfactants, dissolving aids,suspending agents, isotonizing agents, buffering agents, antiseptics,antioxidants, stabilizers and absorption accelerators.

The dose of the compound according to the present invention for thepharmaceutical use varies depending on symptoms and age of the patients,but it will ordinary be 0.1 mg to 10 g (preferably 1 mg to 2 g) for anoral formulation, 0.01 mg to 10 g (preferably 0.1 mg to 2 g) for anexternal application, and 0.01 mg to 10 g (preferably 0.1 mg to 2 g) foran injection, which is administrated once or divided over two to fourtimes a day.

EXAMPLES

The compound according to the present invention can be produced, forexample, by the methods described in the below Production Examples andExamples. But these Examples are for illustrative purposes, and thecompound according to the present invention is not limited to thefollowing specific Examples in any case.

In the Production Examples and Examples, YMC SIL-60-400/230W was used assilica gel for purification unless otherwise described.

For conditions of purification by LC-MS, the two conditions describedbelow (Gradient Condition 1 or Gradient Condition 2) was used unlessotherwise described.

-   ODS column: CAPCELL PAK C-18-   Solvent-   Solution A: Water-   Solution B: Acetonitrile-   Solution C: 1% trifluoroacetic acid in water-   Flow rate: 30 ml/min-   Stop time: 10 min-   Gradient Condition 1-   0.00 min A: 80%, B: 10%, C: 10%-   7.80 min A: 30%, B: 60%, C: 10%-   8.00 min A: 0%, B: 100%, C: 0%    Gradient Condition 2-   0.00 min A: 80%, B: 10%, C: 10%-   2.00 min A: 70%, B: 20%, C: 10%-   7.50 min A: 40%, B: 50%, C: 10%-   8.00 min A: 0%, B: 100%, C: 0%

Production Example 1 tert-Butyl 3-dimethylaminoazetidine-1-carboxylate

To a solution of 1-Boc-azetidin-3-one (3.45 g) in methanol (175 ml) wereadded a 2M solution of dimethylamine in tetrahydrofuran (21.9 ml),acetic acid (1.73 ml), 10% palladium on carbon (2.15 g), followed bystirring at room temperature under a hydrogen atmosphere for 14 hr. Thecatalyst was removed by filtration and the filtrate was concentratedunder reduced pressure. The residue was partitioned between ethylacetate and a saturated aqueous solution of sodium hydrogencarbonate.The combined organic layer was dried over anhydrous sodium sulfate,which was concentrated to provide the titled compound as a colorless oil(4.07 g, 101%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43 (9H, m), 2.17 (6H, s), 3.01 (1H,m), 3.79 (2H, m), 3.91 (2H, m).

Production Example 2N-[1-(1-Benzylpiperidin-4-yl)azetidin-3-yl]-N,N-dimethylaminetrihydrochloride

tert-Butyl 3-dimethylaminoazetidine-1-carboxylate (7.00 g) was stirredin an ice bath, and trifluoroacetic acid (21.6 ml) was added thereto,followed by stirring in an ice bath for 30 min, then at room temperaturefor 1.5 hr. The reaction mixture was concentrated to provide a crudeproduct of 3-(dimethylamino)azetidine ditrifluoroacetate as a brown oil(ESI-MS (m/z): 101[M+H]⁺). This was dissolved in dichloromethane (350ml), and 1-benzyl-4-piperidone (6.49 ml) was added thereto, followed bystirring at room temperature for 10 min. This was cooled in an ice bath,and sodium triacetoxyborohydride (11.1 g) was added thereto, followed bystirring at room temperature for 2 hr. The reaction mixture wasconcentrated. To the residue were added ethyl acetate (300 ml), brineand potassium carbonate, followed by stirring at room temperature for 20min and liquid-liquid separation was carried out. The aqueous layer wasextracted with ethyl acetate:tetrahydrofuran=1:1. The organic layer wascombined and dried, followed by addition of a 4N solution ofhydrochloric acid in ethyl acetate (26.3 ml). This was concentrated toprovide a crude product of the titled compound as colorless crystals(14.1 g).

ESI-MS (m/z): 274 [M+H]⁺.

Production Example 3N,N-Dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride

To a solution of a crude product ofN-[1-(1-benzylpiperidin-4-yl)azetidin-3-yl]-N,N-dimethylaminetrihydrochloride (14.1 g) in 2-propanol (380 ml)-water (380 ml) wasadded 10% palladium on carbon (5.0 g), followed by stirring at roomtemperature under a hydrogen atmosphere for 12 hr. The catalyst wasremoved by filtration. Concentration of the filtrate provided a crudeproduct of the titled compound as colorless crystals (10.7 g).

ESI-MS (m/z): 184 [M+H]⁺.

Production Example 4 1-(1-Methylazetidin-3-yl)piperazinetrihydrochloride

To a solution of 1-benzylpiperazine (0.500 ml) in methanol (25 ml) wereadded 1-Boc-azetidin-3-one (495 mg), acetic acid (0.182 ml), followed bystirring at room temperature for 5 min. 10% palladium on carbon (308 mg)was added thereto, followed by stirring at room temperature under ahydrogen atmosphere for 15 hr. The catalyst was removed by filtration.The residue was partitioned between ethyl acetate and a saturatedaqueous solution of sodium hydrogencarbonate. The organic layer waswashed with brine, and dried over anhydrous sodium sulfate. This wasconcentrated to provide a crude product of4-benzyl-1-(1-Boc-azetidin-3-yl)piperazine (ESI-MS (m/z): 332 [M+H]⁺).This was dissolved in tetrahydrofuran (10 ml). Lithium aluminum hydride(219 mg) was added thereto while stirring in an ice bath. The mixturewas stirred under a nitrogen atmosphere in an ice bath for 15 min, atroom temperature for 15 min, and was heated to reflux at 100° C. for 3.5hr. The reaction mixture was cooled in an ice bath. Water (0.22 ml), a5N aqueous solution of sodium hydroxide (0.22 ml) and water (1.1 ml)were added thereto, followed by stirring in an ice bath for 1 hr.Insoluble matter was removed by filtration. To the filtrate was added a4N solution of hydrochloric acid in ethyl acetate (2.17 ml), which wasconcentrated to provide a crude product of4-benzyl-1-(1-methylazetidin-3-yl)piperazine trihydrochloride (ESI-MS(m/z): 246[M+H]⁺). This was dissolved in water (25 ml) and 2-propanol(25 ml). 10% palladium on carbon (615 mg) was added thereto, followed bystirring under a hydrogen atmosphere at room temperature for 12 hr. Thecatalyst was removed by filtration. Concentration of the filtrateprovided a crude product of the titled compound as a white solid (382mg).

ESI-MS (m/z): 156 [M+H]⁺.

Production Example 5 tert-Butyl[1-(2-dimethylaminoacetyl)piperidin-4-yl]carbamate

To a solution of 4-(tert-butoxycarbonylamino)piperidine (5.0 g) inN,N-dimethylformamide (70 ml) were added N,N-dimethylglycine (2.97 g),1-hydroxybenzotriazole (3.89 g) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (5.27 g),followed by stirring under a nitrogen atmosphere at room temperature for46 hr. To the reaction mixture were added ethyl acetate (400 ml), brine(200 ml) and a 1N aqueous solution of sodium hydroxide (50 ml), followedby stirring at room temperature for 30 min and liquid-liquid separationwas carried out. The aqueous layer was extracted with ethyl acetate. Theorganic layer was collected, washed with a 1N aqueous solution of sodiumhydroxide and brine in this order, and dried over anhydrous sodiumsulfate. The organic layer was concentrated under reduced pressure toprovide the titled compound as colorless crystals (8.03 g,quantitative).

ESI-MS (m/z): 286 [M+H]⁺.

Production Example 6N-[1-(2-Dimethylaminoethyl)piperidin-4-yl]-N-methylamine

A solution of tert-butyl[1-(2-dimethylaminoacetyl)piperidin-4-yl]carbamate (7.07 g) intetrahydrofuran (100 ml) was stirred under a nitrogen atmosphere in anice bath. Lithium aluminum hydride (280 mg) was added thereto, followedby stirring in an ice bath for 15 min, then at room temperature for 15min. The reaction mixture was heated to reflux at 100° C. under anitrogen atmosphere for 11 hr. The reaction mixture was cooled in an icebath. Water (2.8 ml), a 5N aqueous solution of sodium hydroxide (2.8 ml)and water (14.0 ml) were added thereto in this order, followed bystirring for 2 hr. Insoluble matter was removed by filtration. Thefiltrate was concentrated to provide the titled compound as a yellow oil(4.65 g, quantitative).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.34-1.43 (2H, m), 1.87-1.90 (2H, m),2.02-2.08 (2H, m), 2.25 (6H, s), 2.31-2.50 (7H, m), 2.90 (2H, m),3.14-3.27 (1H, m).

ESI-MS (m/z): 186 [M+H]⁺.

Production Example 7 N,N-Diethyl-N′-methylpropane-1,3-diamine

To a solution of N,N-diethyl-1,3-propanediamine (10.0 ml) andtriethylamine (10.0 ml) in tetrahydrofuran (150 ml) was added dropwisemethyl chloroformate (5.15 ml) while stirring in an ice bath. Afterstirring at room temperature for 30 min, a saturated aqueous solution ofsodium hydrogencarbonate (10 ml) was added to the reaction mixture, andliquid-liquid separation was carried out. The organic layer was driedover anhydrous sodium sulfate, and concentrated under reduced pressure.The residue was dissolved again in ethyl acetate (200 ml), dried overpotassium carbonate, and concentrated under reduced pressure to providea pale yellow oil (8.90 g, ESI-MS (m/z): 189). The residue was dissolvedin tetrahydrofuran (200 ml), and lithium aluminum hydride (2.00 g) wasgradually added thereto while stirring in an ice bath. The reactionmixture was stirred under a nitrogen atmosphere at room temperature for15 min, then at 65° C. for 1.5 hr. The reaction mixture was cooled in anice bath, water (2.0 ml), a 5N aqueous solution of sodium hydroxide (2.0ml) and water (10.0 ml) were added thereto in this order, followed bystirring in an ice bath for 1 hr. Insoluble matter was removed byfiltration and washed with tetrahydrofuran, and the filtrate wasconcentrated under reduced pressure to provide the titled compound as apale yellow oil (9.2 g, 72%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.01 (6H, t, J=7.0 Hz), 1.65 (2H, m),2.42 (3H, s), 2.47 (2H, t, J=7.0 Hz), 2.51 (4H, q, J=7.0 Hz), 2.62 (2H,t, J=7.0 Hz).

ESI-MS (m/z): 145 [M+H]⁺.

Production Example 8 (4-Benzoylpiperazin-1-yl)acetic acid ethyl ester

1-(Ethoxycarbonylmethyl)piperazine (5.1 g) was dissolved intetrahydrofuran (300 ml) under a nitrogen atmosphere, and triethylamine(8.25 ml) and benzoyl chloride (3.44 ml) were added thereto whilestirring in an ice water bath. The reaction mixture was allowed to warmup to room temperature and stirred for 4 hr. The reaction mixture waspartitioned between ethyl acetate (200 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (100 ml). The separated organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (100 ml), water (100 ml) and brine (100 ml), and driedover sodium sulfate. The solvent was removed under reduced pressure toprovide the titled compound as a colorless oil (8.19 g, quantitative).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.28 (3H, t, J=7.2 Hz), 2.20-2.85 (4H,m), 3.26 (2H, m), 3.48 (2H, m), 3.85 (2H, m), 4.19 (2H, m), 7.41 (5H,m).

Production Example 91-(Azetidin-1-yl)-2-(4-benzoylpiperazin-1-yl)ethanone

To (4-benzoylpiperazin-1-yl)acetic acid ethyl ester (8.19 g) were addedmethanol (300 ml) and water (50 ml), and lithium hydroxide (1.34 g) wasadded thereto in an ice water bath, followed by stirring for 10 min. Thereaction mixture was allowed to warm up to room temperature and stirredfor 24 hr. After addition of 1N hydrochloric acid (55.9 ml), thereaction mixture was concentrated under reduced pressure, and ethanol(200 ml) was added to the resultant residue. Precipitated insolublematter was filtered through celite. The filtrate was concentrated toprovide a crude product of (4-benzoylpiperazin-1-yl)acetic acid as awhite solid (8.6 g). To (4-benzoylpiperazin-1-yl)acetic acid (2 g) wasadded N,N-dimethylformamide (80 ml) under a nitrogen atmosphere at roomtemperature, and azetidine hydrochloride (1.51 g), triethylamine (4.49ml), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (3.09g) and 1-hydroxybenzotriazole (2.18 g) were added thereto in this order,followed by stirring at room temperature for 66 hr. Liquid-liquidseparation was carried out after addition of ethyl acetate (100 ml) anda saturated aqueous solution of sodium hydrogencarbonate (50 ml) to thereaction mixture. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate (50 ml), water (50 ml) and brine(50 ml) in this order, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the resultant residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; ethyl acetate). Fractions containing the target compound wereconcentrated under reduced pressure, the resultant residue was suspendedin diethyl ether (10 ml). The solid was collected by filtration, anddried under aeration to provide the titled compound as white powder(731.5 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.40-2.80 (6H, m), 3.03 (2H, s), 3.47(2H, m), 3.83 (2H, m), 4.06 (2H, m), 4.22 (2H, m), 7.30-7.50 (5H, m).

Production Example 10 1-[2-(Azetidin-1-yl)ethyl]-4-benzylpiperazine

Lithium aluminum hydride (405 mg) was suspended in tetrahydrofuran (10ml) under a nitrogen atmosphere while stirring in an ice water bath, and1-(azetidin-1-yl)-2-(4-benzoylpiperazin-1-yl)ethanone (730 mg) andtetrahydrofuran (5 ml×3) were added thereto. The reaction mixture wasstirred at 60° C. for 3 hr. After the reaction mixture was allowed tocool down to room temperature, water (0.4 ml), a 5N aqueous solution ofsodium hydroxide (0.4 ml) and water (1.2 ml) was added thereto, followedby stirring for 13 hr. Insoluble matter in the reaction mixture wasfiltered through celite, and washed with ethyl acetate (100 ml). Thesolvent was removed under reduced pressure to provide a crude product ofthe titled compound as a pale yellow oil (687 mg).

ESI-MS (m/z): 260 [M+H]⁺.

Production Example 11 1-[2-(Azetidin-1-yl)ethyl]piperazinetrihydrochloride

1-[2-(Azetidin-1-yl)ethyl]-4-benzylpiperazine (687 mg) was dissolved inmethanol (30 ml), and 20% palladium hydroxide on carbon (372 mg) wasadded thereto, followed by stirring under pressurized hydrogenatmosphere (0.4 MPa) for 10 hr. The catalyst was removed by filtrationand washed with methanol. To the filtrate was added a 4N solution ofhydrochloric acid in ethyl acetate (1.33 ml), followed by stirring.Excess hydrochloric acid was removed under reduced pressure whilestirring. The solvent was removed under reduced pressure to provide thetitled compound as a pale brown oil (736 mg, quantitative).

ESI-MS (m/z): 170 [M+H]⁺.

Production Example 12 2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine

2-Amino-4-chloropyridine (8.00 g) was dissolved in N-methylpyrrolidone(65 ml), and 2-fluoro-4-nitrophenol (19.55 g) andN,N-diisopropylethylamine (43.36 ml) were added thereto, followed bystirring at 160° C. for 41 hr. The reaction mixture was allowed to cooldown to room temperature, and was partitioned between ethylacetate-tetrahydrofuran (1:1) and a 2N aqueous solution of sodiumhydroxide. The organic layer was washed with water and brine in thisorder. The aqueous layer was re-extracted with ethyl acetate, and thecombined organic layer was dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, the residue was purified bysilica gel column chromatography (eluent; hexane:ethyl acetate=1:2, thenethyl acetate). Fractions containing the target compound wereconcentrated, and crystals were precipitated by addition of ethylacetate to the residue. The crystals were collected by filtration anddried under aeration to provide the titled compound as opalescentcrystals (3.02 g, 20%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.52 (2H, brs), 6.05 (1H, d, J=1.6 Hz),6.30 (1H, dd, J=1.6, 5.6 Hz), 7.20-7.30 (1H, m), 8.02 (1H, d, J=5.6 Hz),8.05-8.15 (2H, m).

Production Example 133-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (200 mg) was dissolved intetrahydrofuran (8 ml) under a nitrogen atmosphere, and triethylamine(0.336 ml) and phenyl chloroformate (0.302 ml) were added dropwisethereto, followed by stirring at room temperature for 30 min. Thereaction mixture was concentrated under reduced pressure, the resultantresidue was dissolved in N,N-dimethylformamide (5 ml), andN-methyl-N-(1-methylpiperidin-4-yl)amine (0.467 ml) was added at roomtemperature, followed by stirring for 4 hr. The reaction mixture waspartitioned between ethyl acetate and a saturated aqueous solution ofammonium chloride. The organic layer was washed with a saturated aqueoussolution of ammonium chloride, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure, the resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate). Thesolvent was concentrated under reduced pressure and dried under reducedpressure to provide the titled compound as a yellow solid (245 mg,75.5%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.70 (2H, m), 1.79 (2H, m),2.04-2.13 (2H, m), 2.29 (3H, s), 2.88-2.98 (5H, m), 4.09-4.22 (1H, m),6.66 (1H, dd, J=2.4, 5.6 Hz), 7.26-7.35 (1H, m), 7.74-7.78 (1H, m),8.06-8.13 (2H, m), 8.13-8.19 (2H, m).

Production Example 143-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea

3-[4-(2-Fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea(243 mg) was dissolved in tetrahydrofuran (6 ml)-methanol (6 ml), and10% palladium on carbon (128 mg) was added thereto, followed by stirringunder a hydrogen atmosphere for 3 hr. The atmosphere in the reactionvessel was replaced with nitrogen, and the catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated underreduced pressure, and the resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate) andconcentrated under reduced pressure to provide the titled compound aspale yellow powder (175 mg, 78.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.70 (2H, m), 1.78 (2H, m),1.98-2.18 (2H, m), 2.20-2.38 (3H, m), 2.82-3.02 (5H, m), 3.75 (2H, m),4.08-4.26 (1H, m), 6.45 (1H, dd, J=3.2, 8.4 Hz), 6.47-6.66 (2H, m), 6.97(1H, m), 7.17 (1H, brs), 7.65 (1H, d, J=2.0 Hz), 8.03 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 374 [M+H]⁺.

Production Example 15 Ethyl 4-chloropyridine-2-carboxylate

A mixture of 4-chloropyridine-2-carboxylic acid (39.4 g) and thionylchloride (64 ml) was heated and stirred at 100° C. under a nitrogenatmosphere for 6 hr. The reaction mixture was allowed to cool down toroom temperature. This was concentrated under reduced pressure anddistilled azeotropically with toluene. The resultant residue wasgradually added to ethanol while stirring in an ice bath. The reactionmixture was stirred at room temperature for 25.5 hr. The reactionmixture was concentrated under reduced pressure. To the residue wasadded a saturated aqueous solution of sodium hydrogencarbonate andextracted with ethyl acetate. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure to provide the titled compound as a brown oil (38.8 g, 83.6%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.46 (3H, t, J=7.2 Hz), 4.50 (2H, q,J=7.2 Hz), 7.49 (1H, dd, J=2.0, 5.2 Hz), 8.15 (1H, d, J=2.0 Hz), 8.67(1H, d, J=5.2 Hz).

Production Example 16 Ethyl4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate

To ethyl 4-chloropyridine-2-carboxylate (19.4 g) were added3-fluoro-4-nitrophenol (24.7 g) and chlorobenzene (7.0 ml), followed byheating and stirring under a nitrogen atmosphere at 120° C. for 4 hr.The reaction mixture was allowed to cool down to room temperature. Ethylacetate (400 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (400 ml) were added thereto, followed by stirring atroom temperature for 27 hr. Stirring was stopped and the aqueous layerwas separated. To the organic layer was added again a saturated aqueoussolution of sodium hydrogencarbonate, followed by stirring at roomtemperature for 2 days. Stirring was stopped and the aqueous layer wasseparated. The aqueous layer was extracted with ethyl acetate (300 ml).The organic layers were combined and washed with brine. The organiclayer was dried over anhydrous sodium sulfate and concentrated underreduced pressure. The residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=2:1, 1:1, then ethylacetate). Fractions containing the target compound were concentrated toprovide the titled compound as a brown oil (12.9 g, 40.2%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.45 (3H, t, J=7.2 Hz), 4.49 (2H, q,J=7.2 Hz), 6.97-7.01 (2H, m), 7.16 (1H, dd, J=2.4, 5.6 Hz), 7.79 (1H, d,J=2.4 Hz), 8.20 (1H, m), 8.76 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 329 [M+Na]⁺.

Production Example 174-(4-Benzyloxycarbonylamino-3-fluorophenoxy)pyridine-2-carboxylic acid

To a solution of ethyl 4-(3-fluoro-4-nitrophenoxy)pyridine-2-carboxylate(8.56 g) in ethanol (150 ml) was added 20% palladium hydroxide on carbon(1.0 g), followed by stirring under a hydrogen atmosphere at roomtemperature for 9.5 hr. The catalyst was removed by filtration. To thefiltrate was added a 4N solution of hydrochloric acid in ethyl acetate(14 ml) and concentrated. Concentration was stopped before dryness.Water (75 ml), acetone (150 ml) and sodium hydrogencarbonate (11.8 g)was added thereto. This was cooled in an ice bath, and benzyloxycarbonylchloride (6.00 ml) was added. The reaction mixture was stirred at roomtemperature for 4 hr. The reaction mixture was concentrated underreduced pressure. The residue was extracted with ethyl acetate. Theorganic layer was washed with brine and dried over anhydrous sodiumsulfate. This was concentrated under reduced pressure, and the residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=1:1, 1:2, then ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure. The resultant solidwas suspended in hexane and allowed to stand for a while, then thesupernatant was removed by using a pipette. This residue was dried toprovide ethyl4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridine-2-carboxylate aspale yellow solid (7.51 g, 65.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43 (3H, m), 4.45-4.52 (2H, m), 5.24(2H, s), 6.87-6.92 (2H, m), 6.99 (1H, dd, J=2.4, 5.6 Hz), 7.35-7.45 (6H,m), 7.65 (1H, d, J=2.4 Hz), 8.19 (1H, m), 8.60 (1H, d, J=5.6 Hz).

Ethyl 4-(4-benzyloxycarbonylamino-3-fluorophenyl)pyridine-2-carboxylate(7.95 g) was dissolved in ethanol (120 ml), and water (25 ml) was addedthereto. Lithium hydroxide (783 mg) was added thereto while stirring atroom temperature, followed by stirring at room temperature for 1 hr. Tothe reaction mixture was added 1N hydrochloric acid (60 ml) andconcentrated under reduced pressure. After concentration, precipitatedcrystals in the reaction mixture were collected by filtration and washedwith water. The crystals were dissolved in ethylacetate-tetrahydrofuran, and dried over anhydrous sodium sulfate. Thesolution after drying was concentrated under reduced pressure. Theresultant crystals were suspended in hexane and collected by filtration.The crystals were dried to provide the target compound as pale yellowcrystals (5.04 g, 72.0%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.18 (2H, s), 7.08 (1H, m), 7.23 (1H,m), 7.24-7.46 (8H, m), 7.75 (1H, m), 8.59 (1H, d, J=5.6 Hz), 9.59 (1H,s).

Production Example 18 tert-Butyl[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]carbamate

To a suspension of4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridine-2-carboxylic acid(5.04 g) in tert-butanol (50 ml) was added triethylamine (4.6 ml) atroom temperature, followed by stirring. Diphenylphosphoryl azide (3.13ml) was added thereto at room temperature, followed by stirring under anitrogen atmosphere at room temperature for 30 min. Then the reactionmixture was heated and stirred at 90° C. for 30 min and at 100° C. for 4hr. The reaction mixture was allowed to cool down to room temperature.Ethyl acetate (25 ml) was added thereto, and the reaction mixture wasstirred in an ice bath for 30 min. Precipitated crystals were collectedby filtration and washed with diethyl ether. These crystals were driedunder aeration at room temperature for 1 hr to provide the titledcompound as colorless crystals (3.92 g, 65.5%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.42 (9H, s), 5.17 (2H, s), 6.62 (1H,dd, J=2.4, 5.6 Hz), 7.01 (1H, dd, J=2.2, 8.8 Hz), 7.21 (1H, dd, J=2.2,11.2 Hz), 7.35-7.42 (6H, m), 7.70 (1H, m), 8.14 (1H, d, J=5.6 Hz), 9.53(1H, s), 9.83 (1H, s).

Production Example 19 Benzyl[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate

A 4N solution of hydrochloric acid in ethyl acetate (120 ml) was cooledin an ice bath. tert-Butyl[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]carbamate(3.92 g) was added thereto while stirring, followed by stirring in anice bath for 10 min. The reaction mixture was then stirred at roomtemperature for 3.5 hr. The reaction mixture was concentrated underreduced pressure. Ethyl acetate (150 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (70 ml) were added thereto, andliquid-liquid separation was carried out. The aqueous layer wasextracted with ethyl acetate (50 ml). The combined organic layer waswashed with brine and dried over anhydrous sodium sulfate. The organiclayer after drying was concentrated under reduced pressure. Theresultant crystals were suspended in a mixed solvent of hexane-ethylacetate (5:1). The crystals were collected by filtration and washed witha mixed solvent of hexane-ethyl acetate (5:1). The crystals were suckedto dryness at room temperature to provide the titled compound as paleyellow crystals (2.93 g, 95.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.49 (2H, m), 5.23 (2H, s), 5.95 (1H,d, J=2.0 Hz), 6.26 (1H, dd, J=2.0, 6.0 Hz), 6.84-6.90 (2H, m), 7.00 (1H,m), 7.34-7.42 (5H, m), 7.94 (1H, d, J=6.0 Hz), 8.10 (1H, m).

ESI-MS (m/z): 354 [M+H]⁺.

Production Example 20 Phenyl[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-n2-yl]-N-phenoxycarbonylcarbamate

To a solution of benzyl[4-(2-aminopyridin-4-yloxy)-2-fluorophenyl]carbamate (1.25 g) intetrahydrofuran (100 ml) were added triethylamine (1.48 ml) and phenylchloroformate (1.11 ml), followed by stirring at room temperature for 1hr. The reaction mixture was partitioned between ethyl acetate and a 1Naqueous solution of sodium hydroxide. The organic layer was washed withbrine, dried over anhydrous sodium sulfate. The solvent was removed toprovide a crude product of phenylN-[4-(4-benzyloxycarbonylamino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamateas a brown oil (ESI-MS (m/z): 616 [M+Na]⁺). This was dissolved intetrahydrofuran (200 ml), 20% palladium hydroxide (497 mg) was addedthereto, and the mixture was stirred under a hydrogen atmosphere at roomtemperature for 4 hr. The catalyst was removed by filtration and washedwith tetrahydrofuran. The filtrate was concentrated to 20 ml to providea solution of phenylN-[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(ESI-MS (m/z): 482 [M+Na]⁺, 941 [2M+Na]⁺) in tetrahydrofuran. This wasdissolved in N,N-dimethylformamide (50 ml).1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.58 g),benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(3.13 g) and triethylamine (0.987 ml) were added thereto, followed bystirring at room temperature for 13.5 hr. The reaction mixture waspartitioned between ethyl acetate and brine. The organic layer waswashed with a 1N aqueous solution of sodium hydroxide and brine in thisorder, and dried over anhydrous sodium sulfate. This was concentrated,and the residue was purified by silica gel column chromatography(heptane:ethyl acetate=3:2, 1:1 then 1:2) to provide the titled compoundas colorless foam (940 mg, 40.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.68-1.76 (4H, m), 6.90 (1H, dd, J=2.4,5.6 Hz), 6.95 (1H, m), 6.98 (1H, m), 7.03-7.07 (3H, m), 7.18 (4H, d,J=8.4 Hz), 7.25 (2H, m), 7.38 (4H, m), 7.48 (2H, m), 8.27 (1H, m), 8.46(1H, d, J=5.6 Hz), 8.75 (1H, s), 9.40 (1H, s).

ESI-MS (m/z): 687 [M+Na]⁺.

Production Example 21 Methyl 4-chloropyridine-2-carboxylate

To thionyl chloride (500 ml) stirred at room temperature was graduallyadded picolinic acid (200 g). The reaction mixture was stirred under anitrogen atmosphere at 85° C. for 20 min and further at 100° C. for 157hr. The reaction mixture was allowed to cool down to room temperature,then thionyl chloride was removed under reduced pressure. Methanol (500ml) was gradually added to the residue while stirring in an ice bath.The reaction mixture was stirred in an ice bath for 1 hr, then at roomtemperature for 17.5 hr. The reaction mixture was concentrated underreduced pressure, and the residue was partitioned between ethylacetate:tetrahydrofuran=2:1 (1.0 l) and a 1N aqueous solution of sodiumhydroxide (500 ml). The aqueous layer was extracted twice with ethylacetate (500 ml). The combined organic layer was washed with brine (500ml) and dried over anhydrous sodium sulfate. The solvent was removed,and hexane (200 ml) and diethyl ether (40 ml) were added to theresultant residue and stirred at room temperature for 13 hr. Theprecipitated solid was collected by filtration, washed twice with amixed solvent of hexane (100 ml)-diethyl ether (20 ml), and dried underaeration to provide the titled compound as a pale yellow solid (182 g,65.2%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 3.99 (3H, s), 7.83 (1H, dd, J=2.0,5.2 Hz), 8.09 (1H, d, J=2.0 Hz), 8.70 (1H, d, J=5.2 Hz).

Production Example 22 4-(4-Amino-2-fluorophenoxy)pyridine-2-carboxylicacid methyl ester dihydrochloride

4-Chloropyridine-2-carboxylic acid methyl ester (30 g) and2-fluoro-4-nitrophenol (41.2 g) were dissolved in chlorobenzene (24 ml),followed by stirring under a nitrogen atmosphere at 120° C. for 4 hr.The reaction mixture was allowed to cool down to room temperature,methanol (100 ml) was added, and stirred for 30 min. The solvent wasremoved under reduced pressure, then the resultant residue waspartitioned between ethyl acetate (300 ml) and a 1N aqueous solution ofsodium hydroxide (150 ml). The separated organic layer was washed with a1N aqueous solution of sodium hydroxide (100 ml) and brine (150 ml) anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, ethanol (200 ml) was added to the resultant residue,followed by stirring for 30 min. The solid was collected by filtrationand the filtrate was purified by silica gel column chromatography (YMC,SIL-60-400/230W, eluent; heptane:ethyl acetate=1:1). Fractionscontaining the target compound were concentrated under reduced pressure,the resultant solid was combined to the solid above to provide4-(2-fluoro-4-nitrophenoxy)pyridine-2-carboxylic acid methyl ester as apale brown solid (20.0 g, 40.0%).

The above purified product (9.90 g) was dissolved in methanol (340 ml)and tetrahydrofuran (340 ml), 20% palladium hydroxide on carbon (2.4 g)was added thereto, followed by stirring under a hydrogen atmosphere for16 hr. The atmosphere in the reaction vessel was replaced with nitrogen,and the catalyst was removed by filtration and washed with methanol. A4N solution of hydrochloric acid in ethyl acetate (4.18 ml) was added tothe filtrate, and concentration under reduced pressure provided a crudeproduct of the titled compound as a pale yellow solid (11.5 g).

ESI-MS (m/z): 263 [M+H]⁺

Production Example 234-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acidmethyl ester

4-(4-amino-2-fluorophenoxy)pyridine-2-carboxylic acid methyl ester (11.5g) was dissolved in acetone (340 ml) and water (170 ml). To the reactionmixture was added sodium hydrogencarbonate (17.3 g), then benzylchloroformate (9.79 ml) while stirring in an ice water bath, followed bystirring for 15 min. The reaction mixture was allowed to warm up to roomtemperature, then stirred for 2 hr. To the reaction mixture cooled in anice water bath was further added benzyl chloroformate (2.45 ml),followed by stirring for 18 hr. The reaction mixture was concentratedunder reduced pressure, and to the resultant residue were added ethylacetate (500 ml) and brine (200 ml), and liquid-liquid separation wascarried out. The separated organic layer was washed with water (100 ml)and brine (200 ml), and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, the resultant solid was suspended inethyl acetate (50 ml) and hexane (30 ml). The solid was collected byfiltration and dried under aeration to provide the titled compound as apale yellow solid (9.6 g, 70.6%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.95-4.10 (3H, m), 5.23 (2H, m), 6.84(1H, m), 7.00 (1H, m), 7.11 (2H, m), 7.34-7.50 (5H, m), 7.56 (1H, m),7.62 (1H, m), 8.59 (1H, m).

Production Example 244-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acid

4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acidmethyl ester (10.7 g) was dissolved in methanol (450 ml) andN,N-dimethylformamide (150 ml), and water (75 ml) and lithium hydroxide(1.36 g) were added thereto, followed by stirring at room temperaturefor 1 hr. 1N hydrochloric acid (100 ml) was added thereto, then thereaction mixture was concentrated under reduced pressure andliquid-liquid separation was carried out after addition of ethyl acetate(500 ml), and the precipitated solid was collected by filtration. Theresultant solid was washed with water and hexane, and dried underaeration. The organic layer of the filtrate obtained above was washedwith water (100 ml×2) and brine (200 ml) and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresultant solid was washed with water and hexane and dried underaeration. This solid was combined with the solid obtained above, anddried at 60° C. overnight to provide the titled compound as white powder(9.53 g, 92.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.32 (1H, brs), 5.19 (2H, s), 7.21 (1H,m), 7.25-7.58 (8H, m), 7.64 (1H, d, J=12.8 Hz), 8.59 (1H, d, J=5.6 Hz),10.18 (1H, brs).

Production Example 25[4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridin-2-yl]carbamic acidtert-butyl ester

4-(4-Benzyloxycarbonylamino-2-fluorophenoxy)pyridine-2-carboxylic acid(500 mg) was dissolved in tert-butyl alcohol (5 ml), and triethylamine(0.457 ml) and diphenylphosphoryl azide (0.310 ml) were added theretounder a nitrogen atmosphere at room temperature, followed by stirringfor 1.5 hr. The reaction mixture was heated up to 30° C. and stirred for1 hr and at 40° C. for 45 min. The reaction mixture was heated up to 50°C. and stirred for 30 min, then heated up to 60° C. and stirred for 30min. The reaction mixture was heated up to 70° C. and stirred for 30 minand at 80° C. for 30 min. The reaction mixture was heated up to 90° C.and stirred for 1.5 hr, then allowed to cool down to room temperatureand stirred for 15 hr. The reaction mixture was partitioned betweenethyl acetate (50 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (30 ml). The organic layer was washed with water (30ml) and brine (30 ml) in this order and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, the resultantresidue was purified by silica gel column chromatography (Fuji SilysiaNH, eluent; heptane:ethyl acetate=3:2). Fractions containing the targetcompound were concentrated under reduced pressure to give a residue,which was suspended in diethyl ether (3 ml) and hexane (3 ml). The solidwas collected by filtration and dried under aeration to provide thetitled compound as a pale yellow solid (277 mg, 46.6%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.49 (9H, s), 5.22 (2H, s), 6.46 (1H,dd, J=2.0, 6.0 Hz), 6.77 (1H, brs), 6.99-7.14 (2H, m), 7.28-7.48 (7H,m), 7.52 (1H, m), 8.06 (1H, d, J=6.0 Hz).

ESI-MS (m/z): 476 [M+Na]⁺.

Production Example 26[4-(2-Aminopyridin-4-yloxy)-3-fluorophenyl]carbamic acid benzyl ester

To a 4N solution of hydrochloric acid in ethyl acetate (30 ml) was added[4-(4-benzyloxycarbonylamino-2-fluorophenoxy)pyridin-2-yl]carbamic acidtert-butyl ester (510 mg) while stirring in an ice water bath. Thereaction mixture was allowed to warm up to room temperature, followed bystirring for 16 hr. To the reaction mixture were added diethyl ether (10ml) and a 5N aqueous solution of sodium hydroxide (1 ml), followed bystirring for 30 min. The separated organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate (20 ml), water(20 ml) and brine (20 ml), and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, the resultant residue waspurified by silica gel column chromatography (Fuji Silysia NH, eluent;heptane:ethyl acetate=1:2) and fractions containing the target compoundwere concentrated under reduced pressure. To the resultant residue wereadded diethyl ether (4 ml) and hexane (6 ml) to suspend the precipitatedsolid. The solid was collected by filtration and dried under aeration toprovide the titled compound as pale yellow powder (46.6 mg, 11.7%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.35 (2H, brs), 5.19 (2H, m), 6.14 (1H,brs), 6.69 (1H, m), 7.30-7.52 (6H, m), 7.66 (1H, m), 7.83 (1H, m), 7.97(1H, m), 10.24 (1H, brs).

Production Example 27{4-[4-(Benzyloxycarbonylamino)-2-fluorophenoxylpyridin-2-yl}-N-(phenoxycarbonyl)carbamicacid phenyl ester

To a solution of [4-(2-aminopyridin-4-yloxy)-3-fluorophenyl]carbamicacid benzyl ester (1.0 g) in tetrahydrofuran (25 ml) were addedtriethylamine (0.983 ml) and phenyl chloroformate (0.884 ml) in thisorder while stirring in an ice water bath. The reaction mixture wasstirred at room temperature for 30 min. After the reaction mixture wasdiluted with ethyl acetate, a saturated aqueous solution of sodiumhydrogencarbonate was added thereto, and the reaction mixture wasstirred. The organic layer was separated, washed with a saturatedaqueous solution of sodium hydrogencarbonate and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure, and the residue was dried under reduced pressureto provide a crude product of the titled compound as a brown oil (1.945g).

ESI-MS (m/z): 616 [M+Na]⁺.

Production Example 28[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

To a solution of a crude product of{4-[4-(benzyloxycarbonylamino)-2-fluorophenoxy]pyridin-2-yl}-N-(phenoxycarbonyl)carbamicacid phenyl ester (1.945 g) in tetrahydrofuran (100 ml) was added 20%palladium hydroxide on carbon (792 mg), followed by stirring under ahydrogen atmosphere at room temperature for 3 hr. The catalyst wasremoved by filtration and washed with tetrahydrofuran. The filtrate wasconcentrated under reduced pressure, and the residue was dried underreduced pressure to provide a crude product of the titled compound as abrown oil (1.617 g).

ESI-MS (m/z): 482 [M+Na]⁺, 941 [2M+Na]⁺.

Production Example 29[4-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (1.617 g) was dissolved in N,N-dimethylformamide (25ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (1.26 g),triethylamine (0.786 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(2.49 g) were added thereto under a nitrogen atmosphere at roomtemperature, followed by stirring overnight. Liquid-liquid separationwas carried out after addition of ethyl acetate and water to thereaction mixture. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate (3 times) and brine in this orderand dried over anhydrous sodium sulfate. The solvent was removed to giveresidue, which was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=1:1) to provide the titled compound as whitepowder (1.007 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.80 (4H, m), 6.89 (1H, dd, J=2.4,5.6 Hz), 7.00-7.50 (17H, m), 7.75 (1H, dd, J=2.4, 12.0 Hz), 8.14 (1H,brs), 8.44 (1H, d, J=5.6 Hz), 10.05 (1H, brs).

ESI-MS (m/z): 687 [M+Na]⁺.

Production Example 302-{[(4-(Dimethylaminomethyl)piperidin-1-yl)carbonylamino]-4-(2-fluoro-4-nitrophenoxy)pyridine

2-Amino-4-(2-fluoro-4-nitrophenoxy)pyridine (125 mg) was dissolved intetrahydrofuran (2 ml) under a nitrogen atmosphere. While stirring in anice water bath, triethylamine (0.210 ml) and phenyl chloroformate (0.189ml) were added dropwise. After stirring at room temperature for 20 min,the solvent was removed under reduced pressure. To the resultant residuewere added a solution of 4-(dimethylaminomethyl)piperidinedihydrochloride (648 mg) in N,N-dimethylformamide (5.0 ml) andtriethylamine (0.985 ml) under a nitrogen atmosphere at roomtemperature, followed by stirring for 2.5 hr. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a 1N aqueous solution of sodium hydroxide and brine, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure, and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate:heptane=2:1, thenethyl acetate) to provide the titled compound as pale yellow powder (183mg, 87%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10-1.30 (2H, m), 1.60-1.90 (3H, m),2.10-2.20 (2H, m), 2.21 (6H, s), 2.80-3.00 (2H, m), 4.00-4.20 (2H, m),6.64 (1H, dd, J=2.4, 5.6 Hz), 7.26-7.40 (2H, m), 7.72 (1H, d, J=2.4 Hz),8.00-8.20 (3H, m).

Production Example 314-(4-Amino-2-fluorophenoxy)-2-{[4-(dimethylaminomethyl)piperidin-1-yl]carbonylamino}pyridine

2-{[4-(Dimethylaminomethyl)piperidin-1-yl]carbonylamino}-4-(2-fluoro-4-nitrophenoxy)pyridine(183 mg) was dissolved in tetrahydrofuran (20 ml). 20% palladiumhydroxide on carbon (123 mg) was added thereto, followed by stirringunder a hydrogen atmosphere overnight. The catalyst was removed byfiltration and washed with tetrahydrofuran. The filtrate and the washingwere combined and concentrated under reduced pressure, the resultantresidue was dried under reduced pressure to provide the titled compoundas pale yellow powder (167 mg, 98%).

ESI-MS (m/z): 388 [M+H]⁺.

Production Example 32 2-Propyl 4-chloropyridine-2-carboxylate

To 4-chloropyridine-2-carboxylic acid (5.0 g) was added thionyl chloride(10 ml), followed by stirring at 100° C. for 3 hr. The reaction mixturewas allowed to cool down to room temperature, and concentrated underreduced pressure. The residue was added to 2-propanol (50 ml) cooled inan ice water bath, and the reaction mixture was stirred overnight atroom temperature. A saturated aqueous solution of sodiumhydrogencarbonate was added to the reaction mixture, and extracted withethyl acetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate. The solvent was removed under reduced pressureand distilled azeotropically with toluene, and the resultant residue wasdried under reduced pressure to provide the titled compound as a brownoil (6.1 g, 96%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43 (6H, d, J=7.2 Hz), 5.35 (1H, m),7.48 (1H, dd, J=2.4, 5.6 Hz), 8.12 (1H, d, J=2.4 Hz), 8.67 (1H, d, J=5.6Hz).

Production Example 33 2-Propyl 4-(4-nitrophenoxy)pyridine-2-carboxylate

2-Propyl 4-chloropyridine-2-carboxylate (3.13 g) was dissolved inchlorobenzene (9.5 ml). 4-Nitrophenol (3.28 g) was added thereto,followed by stirring at 120° C. for 23 hr. 4-Nitrophenol (1.09 g) wasadded thereto, followed by stirring at 120° C. for 3 hr. The reactionmixture was allowed to cool down to room temperature. Ethyl acetate (50ml) and a 1N aqueous solution of sodium hydroxide (50 ml) were added tothe reaction mixture and stirred. Insoluble matter was precipitated,which was dissolved by addition of THF (50 ml). The organic layer wasseparated, washed with a 1N aqueous solution of sodium hydroxide (50ml×3) and brine (50 ml) in this order, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography(eluent; heptane:ethyl acetate=2:1 to 1:1). Fractions containing thetarget compound were concentrated under reduced pressure, and driedunder reduced pressure to provide the titled compound as pale browncrystals (2.147 g, 45%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43 (6H, d, J=7.2 Hz), 5.34 (1H, m),7.10 (1H, dd, J=2.4, 5.6 Hz), 7.20-7.25 (2H, m), 7.75 (1H, d, J=2.4 Hz),8.31-8.36 (2H, m), 8.72 (1H, d, J=5.6 Hz).

Production Example 344-[4-(Benzyloxycarbonylamino)phenoxy]pyridine-2-carboxylic acid

2-Propyl 4-(4-nitrophenoxy)pyridine-2-carboxylate (4.5 g) was dissolvedin 2-propanol (100 ml)-tetrahydrofuran (50 ml). 20% palladium hydroxideon carbon (1.05 g) was added thereto, followed by stirring overnightunder a hydrogen atmosphere. The catalyst was removed by filtration andwashed with tetrahydrofuran and methanol in this order. To the filtratewas added 5N hydrochloric acid (7 ml), and concentrated under reducedpressure. The resultant residue was dissolved in acetone (100 ml)-water(50 ml). Sodium hydrogencarbonate (8.4 g) was added dropwise to thereaction mixture while stirring in an ice water bath. Then benzylchloroformate (3.5 ml) was added dropwise. The reaction mixture wasallowed to gradually warm up to room temperature and stirred for 2.5 hr.The reaction mixture was concentrated under reduced pressure. Theresidue containing crystals was diluted with water (100 ml). Ashencrystals were collected by filtration, washed with water (50 ml, 3times) and hexane (50 ml, 4 times) in this order, and dried underaeration. Crude crystals (8.17 g) were suspended in ethanol (100ml)-water (20 ml). Lithium hydroxide (718 mg) was added at roomtemperature, followed by stirring overnight. To the reaction mixture wasadded 1N hydrochloric acid (30 ml). The reaction mixture wasconcentrated under reduced pressure. The target compound which isinsoluble was collected by filtration, washed with water,tetrahydrofuran and ethyl acetate in this order. The organic layer ofthe filtrate was separated and concentrated under reduced pressure. Theresultant solid residue and the solid collected by previous filtrationwere combined, and suspended in ethyl acetate:hexane=1:1 (50 ml). Thesolid was collected by filtration, washed with water and diethylether:hexane=1:1. Drying under aeration for 1 hr, and hot-air drying at60° C. for 48 hr provided the titled compound as pale brown powder(5.062 g, 93%).

ESI-MS (neg.) (m/z): 363 [M−H]⁻.

Production Example 35{4-[(4-Benzyloxycarbonylamino)phenoxy]pyridin-2-yl}carbamic acidtert-butyl ester

4-[4-(Benzyloxycarbonylamino)phenoxy]pyridine-2-carboxylic acid (5.03 g)was suspended in tert-butanol (50 ml), and triethylamine (4.81 ml) wasadded thereto at room temperature. Diphenylphosphoryl azide (3.5 ml) wasadded thereto at room temperature while stirring. The reaction mixturewas stirred under a nitrogen atmosphere at room temperature for 30 min.The reaction mixture was stirred under a nitrogen atmosphere at 90° C.for 30 min and at 100° C. for 4 hr. The reaction mixture was allowed tocool down to room temperature while stirring. To the reaction mixture inwhich crystals were suspended, was added tert-butyl methyl ether (100ml), followed by stirring overnight at room temperature. The crystalswere collected by filtration and washed with diethyl ether to providethe titled compound as white crystals (4.609 g, 77%). The filtrate wasconcentrated under reduced pressure, and the resultant brown oil wasdissolved in ethyl acetate (100 ml), washed with a 1N aqueous solutionof sodium hydroxide (50 ml, twice) and brine (50 ml) and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. Crystals (impurities) were precipitated by addition of ethylacetate (15 ml) to the resultant residue (3.13 g). The crystals(impurities) were removed by filtration. The filtrate was concentratedunder reduced pressure, and crystals were precipitated by addition ofethyl acetate (5 ml) to the resultant residue. The crystals werecollected by filtration and washed with small quantity of diethyl etherto provide the titled compound as white crystals (493 mg, 8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.49 (9H, s), 5.22 (2H, s), 6.45 (1H,dd, J=2.4, 5.6 Hz), 6.70 (1H, brs), 7.02-7.07 (2H, m), 7.30-7.45 (8H,m), 7.52 (1H, brs), 8.04 (1H, d, J=5.6 Hz).

Production Example 36 [4-(2-Aminopyridin-4-yloxy)phenyl]carbamic acidbenzyl ester

To {4-[(4-benzyloxycarbonylamino)phenoxy]pyridin-2-yl}carbamic acidtert-butyl ester (5.087 g) was added a 4N solution of hydrochloric acidin ethyl acetate (75 ml) in an ice water bath, followed by stirring inan ice water bath for 10 min, then at room temperature for 24 hr.Hydrochloric acid was removed from the reaction mixture under reducedpressure. The residue was diluted with ethyl acetate and cooled in anice water bath, and a 2N aqueous solution of sodium hydroxide (100 ml)was added thereto. The organic layer was separated, washed with brineand dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. Crystals were precipitated by addition oftert-butyl methyl ether (20 ml)-heptane (40 ml) to the residue. Thecrystals were collected by filtration and dried under aeration toprovide the titled compound as white crystals (3.159 g, 81%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.38 (2H, brs), 5.22 (2H, s), 5.92 (1H,d, J=2.4 Hz), 6.27 (1H, dd, J=2.4, 5.6 Hz), 6.72 (1H, brs), 7.02-7.06(2H, m), 7.30-7.50 (7H, m), 7.92 (1H, d, J=5.6 Hz).

Production Example 37{4-[4-(Benzyloxycarbonylamino)phenoxy]pyridin-2-yl}-N-(phenoxycarbonyl)carbamicacid phenyl ester

To a solution of [4-(2-aminopyridin-4-yloxy)phenyl]carbamic acid benzylester (500 mg) in tetrahydrofuran (15 ml) were added triethylamine(0.519 ml) and phenyl chloroformate (0.467 ml) while stirring in an icewater bath. The reaction mixture was stirred at room temperature for 30min. The reaction mixture was partitioned between ethyl acetate (50 ml)and a saturated aqueous solution of sodium hydrogencarbonate (20 ml).The separated organic layer was washed with a saturated aqueous solutionof sodium hydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) inthis order, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure to provide a crude product of thetitled compound as brown foam (935.6 mg).

ESI-MS (m/z): 598 [M+Na]⁺.

Production Example 38[4-(4-Aminophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenylester

To a crude product of{4-[4-(benzyloxycarbonylamino)phenoxy]pyridin-2-yl}-N-(phenoxycarbonyl)carbamicacid phenyl ester (936 mg) dissolved in tetrahydrofuran (60 ml) wasadded 20% palladium hydroxide on carbon (209 mg), followed by stirringunder a hydrogen atmosphere at room temperature for 5 hr. The catalystwas removed by filtration and washed with tetrahydrofuran. The solventwas removed under reduced pressure to provide a crude product of thetitled compound as a brown oil (820 mg).

ESI-MS (m/z): 442 [M+Na]⁺, 905 [2M+Na]⁺.

Production Example 39[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-aminophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic acid phenylester (820 mg) was dissolved in N,N-dimethylformamide (15 ml).1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (830 mg),triethylamine (0.519 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.65 g) were added in this order under a nitrogen atmosphere at roomtemperature, followed by stirring for 15.5 hr. Liquid-liquid separationwas carried out after addition of ethyl acetate and a saturated aqueoussolution of sodium hydrogencarbonate to the reaction mixture. Theresultant organic layer was washed with brine and dried over anhydroussodium sulfate. The solvent was evaporated under reduced pressure togive residue, which was purified by silica gel column chromatography(eluent; heptane:ethyl acetate=2:3 to 1:1). Fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white foam (845.8 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.90 (4H, m), 6.89 (1H, dd, J=2.0,5.6 Hz), 7.00-7.32 (11H, m), 7.32-7.42 (4H, m), 7.42-7.54 (2H, m), 7.61(2H, m), 8.43 (1H, d, J=5.6 Hz), 8.61 (1H, brs), 9.39 (1H, brs).

ESI-MS (m/z): 669 [M+Na]⁺.

Production Example 40 6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine

2-Fluoro-4-nitrophenol (1.736 g) was dissolved in dimethyl sulfoxide (10ml), and sodium hydride (400 mg) was added thereto, followed by stirringfor 20 min. Then, 4-Amino-6-chloropyrimidine (648 mg) was added theretoand stirred at 100° C. for 45 min. The reaction mixture was heated up to120° C. and stirred for 1 hr 25 min. The reaction mixture was thenheated up to 140° C. and stirred overnight. The reaction mixture wasallowed to cool down to room temperature, a 1N aqueous solution ofsodium hydroxide (10 ml) was added thereto and stirred, then extractedwith ethyl acetate. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure to give residue, which was purified by silica gelcolumn chromatography (eluent; hexane:ethyl acetate=1:2). The solventwas concentrated under reduced pressure, the resultant residue wassuspended in diethyl ether (7 ml)-hexane (3.5 ml). The solid wascollected by filtration and dried under aeration to provide the titledcompound as pale brown powder (201 mg, 16.0%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 6.02 (1H, m), 7.06 (2H, brs), 7.60(1H, dd, J=8.0, 8.8 Hz), 8.04 (1H, m), 8.10-8.19 (1H, m), 8.30 (1H, dd,J=2.0, 10.0 Hz).

Production Example 41[6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-yl]carbamic acid phenyl ester

6-(2-Fluoro-4-nitrophenoxy)pyrimidin-4-ylamine (1 g) was dissolved intetrahydrofuran (40 ml) under a nitrogen atmosphere, and triethylamine(1.67 ml) and phenyl chloroformate (1.51 ml) were added thereto in anice water bath. The reaction mixture was allowed to warm up to roomtemperature, and stirred for 1 hr. The reaction mixture was partitionedbetween ethyl acetate (200 ml) and a saturated aqueous solution ofsodium hydrogencarbonate (100 ml). The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate (100 ml), water(100 ml) and brine (100 ml) in this order, and dried over anhydroussodium sulfate. To the resultant residue was added tetrahydrofuran (40ml), and a 1N aqueous solution of sodium hydroxide (4 ml) was addedwhile stirring in an ice water bath, followed by stirring for 30 min.The reaction mixture was allowed to warm up to room temperature andstirred for 1 hr. After addition of 1N hydrochloric acid (4 ml), thereaction mixture was partitioned between tetrahydrofuran (100 ml) and asaturated aqueous solution of sodium hydrogencarbonate (50 ml). Theorganic layer was washed with water (50 ml) and brine (100 ml) in thisorder and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure to give residue (4.3 g), to which was added ethylacetate (20 ml), and allowed to stand for 4 days. The precipitated solidwas collected by filtration and dried under aeration to provide thetitled compound as pale yellow powder (399 mg, 26.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 7.16-7.25 (2H, m), 7.25-7.35 (1H, m),7.36-7.50 (3H, m), 7.72 (1H, m), 8.04-8.18 (2H, m), 8.50 (1H, m), 9.18(1H, brs).

ESI-MS (neg.) (m/z): 369 [M−H]⁻

Production Example 42[6-(4-Amino-2-fluorophenoxy)pyrimidin-4-yl]carbamic acid phenyl ester

To a solution of 6-(2-fluoro-4-nitrophenoxy)pyrimidin-4-yl]carbamic acidphenyl ester (394 mg) in tetrahydrofuran (20 ml) was added 20% palladiumhydroxide on carbon (149 mg), followed by stirring under a hydrogenatmosphere at room temperature for 15 hr. The catalyst was removed byfiltration and washed with tetrahydrofuran. The solvent was removedunder reduced pressure to provide a crude product of the titled compoundas a white solid (303 mg)

ESI-MS (m/z): 341 [M+H]⁺, 363 [M+Na]⁺

Production Example 43[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamicacid phenyl ester

A crude product of [6-(4-amino-2-fluorophenoxy)pyrimidin-4-yl]carbamicacid phenyl ester (303 mg) was dissolved in N,N-dimethylformamide (5ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (497 mg),triethylamine (0.310 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(984 mg) were added in this order under a nitrogen atmosphere at roomtemperature, followed by stirring for 5 hr. Liquid-liquid separation wascarried out after addition of ethyl acetate and a saturated aqueoussolution of sodium hydrogencarbonate to the reaction mixture. Theresultant organic layer was washed with brine and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure to giveresidue, which was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=2:3 to 1:1). Fractions containing the targetcompound were concentrated under reduced pressure, the resultant residuewas purified again by silica gel column chromatography (eluent;heptane:ethyl acetate=2:3 to 1:1). Fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as white powder (100.4 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.30-1.80 (4H, m), 7.00-7.10 (2H, m),7.10-7.35 (5H, m), 7.35-7.52 (4H, m), 7.58 (1H, s), 7.70 (1H, dd, J=1.6,12.0 Hz), 8.38 (1H, brs), 8.49 (1H, s), 8.69 (1H, brs), 9.57 (1H, brs).

ESI-MS (m/z): 568 [M+Na]⁺.

Production Example 44 1-(Benzyloxycarbonyl)cyclopropanecarboxylic acid

1,1-Cyclopropanedicarboxylic acid (5.02 g) was dissolved intetrahydrofuran (50 ml) under a nitrogen atmosphere, and triethylamine(5.38 ml) was added dropwise thereto while stirring in an ice waterbath. After stirring at the same temperature for 30 min, thionylchloride (2.82 ml) was added dropwise while stirring in an ice waterbath. After stirring at the same temperature for 30 min, a solution ofbenzyl alcohol (4.39 ml) in tetrahydrofuran (25 ml) was added whilestirring in an ice water bath, and the reaction mixture was allowed togradually warm up to room temperature, followed by stirring overnight.To the reaction mixture was added a 2N aqueous solution of sodiumhydroxide (100 ml), and tetrahydrofuran was removed under reducedpressure. To the resultant aqueous solution was added tert-butyl methylether (25 ml) and stirred. The organic layer and the aqueous layer wereseparated. The aqueous layer was cooled in an ice water bath, andadjusted to pH 4 with 2N hydrochloric acid (50 ml). Ethyl acetate (150ml) was added thereto and stirred for a while. The organic layer wasseparated, washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed to give residue, which was dried under reducedpressure to provide the titled compound as a pale yellow oil (6.29 g,74%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.30-1.40 (4H, m), 5.15 (2H, s),7.30-7.38 (5H, m).

ESI-MS (m/z): 243 [M+Na]⁺.

Production Example 45[4-(4-{[1-(Benzyloxycarbonyl)cyclopropanecarbonyl]amino}phenoxy)-3-fluoropyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (678 mg) was dissolved in N,N-dimethylformamide (25ml). 1-(benzyloxycarbonyl)cyclopropanecarboxylic acid (815 mg),triethylamine (0.516 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(1.64 g) were added under a nitrogen atmosphere at room temperature,followed by stirring overnight. Liquid-liquid separation was carried outafter addition of ethyl acetate and water to the reaction mixture. Theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (3 times) and brine in this order, and dried overanhydrous sodium sulfate. The solvent was removed, and the resultantresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=2:1) to provide the titled compound as a colorlessoil (928 mg).

ESI-MS (m/z): 684 [M+Na]⁺.

Production Example 461-(Benzyloxycarbonyl)-N-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)cyclopropanecarboxamide

To a solution of[4-(4-{[1-(benzyloxycarbonyl)cyclopropanecarbonyl]amino}phenoxy)-3-fluoropyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (928 mg) in N,N-dimethylformamide (20 ml) was added1-methyl-4-methylaminopiperidine (0.814 ml) at room temperature,followed by stirring for 4 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=98:2). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of tert-butyl methyl ether:heptane=1:5 to the resultantresidue. The solvent was removed under reduced pressure. The solidresidue was dried under reduced pressure to provide the titled compoundas white powder (516 mg, 64%).

ESI-MS (m/z): 576 [M+H]⁺.

Production Example 471-(2-Fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid

To a solution of1-(benzyloxycarbonyl)-N-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)cyclopropanecarboxamide(510 mg) in tetrahydrofuran (20 ml)-methanol (20 ml) was added 20%palladium hydroxide on carbon (377 mg), followed by stirring under ahydrogen atmosphere at room temperature for 24 hr. The catalyst wasremoved by filtration, and washed with tetrahydrofuran-methanol(1:1).The filtrate was concentrated under reduced pressure, and the residuewas dried under reduced pressure to provide the titled compound as whitecrystals (358.7 mg, 83%).

ESI-MS (neg.) (m/z): 484 [M−H]⁻.

Production Example 48[4-(3-Fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (219 mg) was dissolved in N,N-dimethylformamide (5ml). 1-(Phenylcarbamoyl)cyclopropanecarboxylic acid (196 mg),triethylamine (0.133 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(422 mg) were added under a nitrogen atmosphere at room temperature,followed by stirring overnight. Liquid-liquid separation was carried outafter addition of ethyl acetate and water to the reaction mixture. Theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (3 times) and brine in this order, and dried overanhydrous sodium sulfate. The solvent was removed and the resultantresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=3:2) to provide the titled compound as whitepowder (271 mg).

ESI-MS (m/z): 669 [M+Na]⁺.

Production Example 491-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acid

1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved intetrahydrofuran (25 ml) under a nitrogen atmosphere, and triethylamine(2.68 ml) was added dropwise thereto while stirring in an ice waterbath. After stirring at the same temperature for 30 min, thionylchloride (1.4 ml) was added dropwise while stirring in an ice waterbath. After stirring at the same temperature for 30 min, a solution of2,4-difluoroaniline (2.15 ml) in tetrahydrofuran (15 ml) was added whilestirring in an ice water bath, and the reaction mixture was allowed togradually warm up to room temperature and stirred overnight. Afteraddition of a 2N aqueous solution of sodium hydroxide (75 ml) to thereaction mixture, tetrahydrofuran was removed under reduced pressure. Tothe resultant solution was added tert-butyl methyl ether (25 ml),followed by stirring. The organic layer and the aqueous layer wereseparated. The aqueous layer was cooled in an ice water bath, 5Nhydrochloric acid (30 ml) was added and stirred. The precipitated solidwas collected by filtration, and washed with water. Drying underaeration and hot-air drying at 60° C. for 8 hr provided the titledcompound as white powder (2.918 g, 63%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.80-1.95 (4H, m), 6.80-6.95 (2H, m),8.20 (1H, m), 10.69 (1H, brs).

ESI-MS (m/z): 264 [M+Na]⁺.

Production Example 50 1-(2-Fluorophenylcarbamoyl)cyclopropanecarboxylicacid

1,1-Cyclopropanedicarboxylic acid (2.5 g) was dissolved intetrahydrofuran (25 ml) under a nitrogen atmosphere, triethylamine (2.68ml) was added dropwise thereto while stirring in an ice water bath.After stirring at the same temperature for 30 min, thionyl chloride (1.4ml) was added dropwise while stirring in an ice water bath. Afterstirring at the same temperature for 30 min, a solution of2-fluoroaniline (2.04 ml) in tetrahydrofuran (15 ml) was added whilestirring in an ice water bath, and the reaction mixture was allowed togradually warm up to room temperature and stirred overnight. To thereaction mixture was added a 2N aqueous solution of sodium hydroxide (75ml), and tetrahydrofuran was removed under reduced pressure. To theresultant aqueous solution was added tert-butyl methyl ether (25 ml) andstirred. The organic layer and aqueous layer were separated. The aqueouslayer was cooled in an ice water bath, 5N hydrochloric acid (30 ml) wasadded and stirred. The precipitated solid was collected by filtrationand washed with water. Drying under aeration and hot-air drying at 60°C. for 8 hr provided the titled compound as white powder (2.294 g, 54%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.80-1.94 (4H, m), 7.00-7.15 (3H, m),8.26 (1H, m), 10.74 (1H, brs).

ESI-MS (m/z): 246[M+Na]⁺.

Production Example 51[4-(4-{[1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (400 mg) was dissolved in N,N-dimethylformamide (5ml). 1-(2,4-Difluorophenylcarbamoyl)cyclopropanecarboxylic acid (241mg), triethylamine (0.139 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(442 mg) were added under a nitrogen atmosphere at room temperature andstirred overnight. Liquid-liquid separation was carried out afteraddition of ethyl acetate and water to the reaction mixture. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (3 times) and brine in this order, and dried overanhydrous sodium sulfate. The solvent was removed and the residue waspurified by silica gel column chromatography (eluent; heptane:ethylacetate=3:2 to 1:1) to provide the titled compound as white powder(116.2 mg).

ESI-MS (m/z): 705 [M+Na]⁺.

Production Example 52[4-(3-Fluoro-4-{[1-(2-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester

A crude product of[4-(4-amino-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (410 mg) was dissolved in N,N-dimethylformamide (5ml). 1-(2-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (223 mg),triethylamine (0.139 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(442 mg) were added under a nitrogen atmosphere at room temperature andstirred overnight. Liquid-liquid separation was carried out afteraddition of ethyl acetate and water to the reaction mixture. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (3 times) and brine in this order, and dried overanhydrous sodium sulfate. The solvent was removed and the resultantresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=3:2 to 1:1) to provide the titled compound aswhite powder (90.6 mg).

ESI-MS (m/z): 687 [M+Na]⁺.

Production Example 53 2-Amino-4-(4-nitrophenoxy)pyridine

2-Amino-4-chloropyridine (2.00 g) was dissolved in N-methylpyrrolidone(31.8 ml) under a nitrogen atmosphere, and 4-nitrophenol (6.51 g) andN,N-diisopropylethylamine (15.9 ml) were added, followed by stirring at150° C. for 3 days. The reaction mixture was allowed to cool down toroom temperature, and partitioned between ethyl acetate and a 1N aqueoussolution of sodium hydroxide (32 ml). The organic layer was washed withwater and brine in this order, and dried over anhydrous sodium sulfate.The solvent was concentrated under reduced pressure, and the resultantresidue was purified by silica gel column chromatography (eluent;hexane:ethyl acetate=1:2 to 1:5). Fractions containing the targetcompound were concentrated under reduced pressure, and the residue wasdried under reduced pressure to provide the titled compound as a brownsolid (764 mg, 21.2%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.54 (2H, brs), 6.11 (1H, s), 6.35 (1H,m), 7.17 (2H, m), 8.05 (1H, d, J=5.6 Hz), 8.27 (2H, m).

Production Example 54 4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylicacid [4-(4-aminophenoxy)pyridin-2-yl]amide

After 2-amino-4-(4-nitrophenoxy)pyridine (160 mg) was dissolved intetrahydrofuran (7 ml) under a nitrogen atmosphere, triethylamine (0.289ml) and phenyl chloroformate (0.260 ml) were added while stirring in anice water bath. The reaction mixture was allowed to warm up to roomtemperature and stirred for 1 hr. The reaction mixture was partitionedbetween ethyl acetate (200 ml) and a saturated aqueous solution ofsodium hydrogencarbonate (50 ml). The separated organic layer was washedwith a saturated aqueous solution of sodium hydrogencarbonate (50 ml),water (50 ml) and brine (100 ml) in this order, and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and tothe resultant residue was added N,N-dimethylformamide (8 ml).4-(Pyrrolidin-1-ylmethyl)piperidine dihydrochloride (668 mg) andtriethylamine (0.772 ml) were added and stirred for 4 hr. The reactionmixture was partitioned between ethyl acetate (100 ml) and a saturatedaqueous solution of ammonium chloride (50 ml). The separated organiclayer was washed with a saturated aqueous solution of ammonium chloride(50 ml), water (50 ml) and brine (50 ml) in this order, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, thenethyl acetate). Fractions containing the target compound wereconcentrated under reduced pressure to provide a crude product of4-(pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid[4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) as a pale yellow oil.4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid[4-(4-nitrophenoxy)pyridin-2-yl]amide (295 mg) was dissolved intetrahydrofuran (7 ml) and methanol (7 ml) under a nitrogen atmosphere,10% palladium on carbon (147 mg) was added and stirred under a hydrogenatmosphere for 10 hr. The atmosphere in the reaction vessel was replacedwith nitrogen, and the catalyst was removed by filtration and washedwith methanol. The filtrate was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate), and fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as white foam (233.7 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10-1.35 (2H, m), 1.60-1.90 (7H, m),2.31 (2H, d, J=6.8 Hz), 2.40-2.50 (4H, m), 2.86 (2H, m), 3.64 (2H, brs),4.00-4.10 (2H, m), 6.47 (1H, dd, J=2.4, 5.6 Hz), 6.70 (2H, d, J=8.8 Hz),6.90 (2H, d, J=8.8 Hz), 7.18 (1H, brs), 7.58 (1H, d, J=2.4 Hz), 7.98(1H, d, J=5.6 Hz).

Production Example 551-[4-(4-Amino-3-chlorophenoxy)pyridin-2-yl]-3-(3-diethylaminopropyl)urea

4-(4-Amino-3-chlorophenoxy)pyridin-2-ylamine (750 mg) was dissolved intetrahydrofuran (30 ml), and triethylamine (0.444 ml) was added thereto.This was cooled in an ice bath, phenyl chloroformate (0.399 ml) wereadded dropwise, and stirred at room temperature for 5 hr. Triethylamine(0.222 ml) and phenyl chloroformate (0.200 ml) were further added andstirred for 40 min. Triethylamine (0.111 ml) and phenyl chloroformate(0.100 ml) were further added and stirred for 30 min. The reactionmixture was concentrated under reduced pressure, and to the residue wereadded N,N-dimethylformamide (10 ml) and 3-(diethylamino)propylamine(2.49 ml), followed by stirring at room temperature for 3 hr.Liquid-liquid separation was carried out after addition of ethyl acetate(50 ml), water (20 ml) and a saturated aqueous solution of sodiumhydrogencarbonate to the reaction mixture. The organic layer was washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasremoved and the resultant residue was dried under reduced pressure toprovide the titled compound as a pale yellow solid (645 mg, 51.8%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.2 Hz), 1.53 (2H, m),2.38 (2H, t, J=7.2 Hz), 2.43 (4H, q, J=7.2 Hz), 3.14 (2H, m), 5.39 (2H,s), 6.47 (1H, dd, J=2.2, 6.0 Hz), 6.80 (1H, d, J=2.2 Hz), 6.84-6.89 (2H,m), 7.08 (1H, d, J=2.2 Hz), 8.00 (1H, d, J=6.0 Hz), 8.19 (1H, brs), 9.07(1H, brs).

Production Example 561-(3-Diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methylurea

To a solution of 4-(2-fluoro-4-nitrophenoxy)pyridin-2-ylamine (300 mg)and triethylamine (0.335 ml) in tetrahydrofuran (30 ml), was addeddropwise phenyl chloroformate (0.226 ml) while stirring in an ice bath,followed by stirring for 0.5 hr. The reaction mixture was concentratedunder reduced pressure, and to the residue were addedN,N-dimethylformamide (6.0 ml) andN,N-diethyl-N′-methyl-1,3-propanediamine (606 mg), followed by stirringat room temperature for 4 hr 45 min. To the reaction mixture was addedethyl acetate (150 ml), washed with a saturated aqueous solution ofsodium hydrogencarbonate, and dried over anhydrous sodium sulfate. Thesolvent was removed and the resultant residue was filtered with silicagel (Fuji Silysia NH, hexane:ethyl acetate=3:1 to 1:1) to provide thetitled compound as a yellow oil (503 mg, 100%).

ESI-MS (m/z): 420 [M+H]⁺.

Production Example 571-(3-Diethylaminopropyl)-3-[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]-1-methylurea

To a solution of1-(3-diethylaminopropyl)-3-[4-(2-fluoro-4-nitrophenoxy)pyridin-2-yl]-1-methylurea(503 mg) in methanol (40 ml)-tetrahydrofuran (20 ml) was added 10%palladium on carbon (200 mg), followed by stirring under a hydrogenatmosphere at room temperature for 12 hr. The catalyst was removed byfiltration and washed with methanol, and the filtrate was concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate, then ethylacetate:methanol=10:1) to provide the titled compound as a yellow oil(467 mg, 85.6%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.97 (6H, t, J=7.2 Hz), 1.68 (2H, m),2.36 (2H, m), 2.52 (4H, m), 2.80 (3H, s), 3.29 (2H, m), 5.43 (2H, m),6.40 (1H, dd, J=2.4, 8.8 Hz), 6.47-6.51 (2H, m), 6.94 (1H, dd, J=8.8,8.8 Hz), 7.29 (1H, d, J=2.4 Hz), 8.02 (1H, d, J=5.6 Hz), 9.33 (1H, s).

Production Example 58 4-(2-Methyl-4-nitrophenoxy)pyridin-2-ylamine

2-Amino-4-chloropyridine (5.0 g), N-methylpyrrolidone (40 ml),2-hydroxy-5-nitrotoluene (11.9 g) and diisopropylethylamine (20.1 g)were placed in a reaction vessel, followed by stirring under a nitrogenatmosphere at 150° C. for 5 days. The reaction mixture was allowed tocool down to room temperature and concentrated under reduced pressure.To the residue was added a saturated aqueous solution of sodiumhydrogencarbonate, followed by stirring overnight at room temperature.Liquid-liquid separation was carried out after addition oftetrahydrofuran (200 ml) to the reaction mixture. The aqueous layer wasextracted with diethyl ether (100 ml). The organic layer was washed withbrine, dried over anhydrous sodium sulfate and concentrated underreduced pressure. The precipitated solid was suspended in diethyl etherand collected by filtration. The solid was washed with diethylether:ethyl acetate=1:1 and dried under aeration to provide the titledcompound as a yellow solid (4.36 g, 45:7%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 2.28 (3H, s), 5.89 (1H, d, J=2.0 Hz),6.04 (2H, brs), 6.19 (1H, dd, J=2.4, 5.6 Hz), 7.23 (1H, d, J=8.8 Hz),7.87 (1H, d, J=5.6 Hz), 8.14 (1H, dd, J=2.8, 8.8 Hz), 8.29 (1H, d, J=2.8Hz).

ESI-MS (m/z): 246 [M+H]⁺.

Production Example 591-(3-Diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea

To a solution of 4-(2-methyl-4-nitrophenoxy)pyridin-2-ylamine (500 mg)and triethylamine (0.569 ml) in tetrahydrofuran (50 ml) was addeddropwise phenyl chloroformate (0.384 ml) while cooling in an ice bath,followed by stirring for 0.5 hr. The reaction mixture was concentratedunder reduced pressure, and to the residue were addedN,N-dimethylformamide (20 ml) and N,N-diethyl-1,3-propanediamine (1.28ml), followed by stirring at room temperature for 2 hr. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with brine, dried over anhydrous sodium sulfate andconcentrated under reduced pressure. The residue was purified by silicagel column chromatography (Fuji Silysia NH, eluent; hexane:ethylacetate=1:1, then ethyl acetate) to provide the titled compound as apale yellow oil (794 mg, 96.9%).

ESI-MS (m/z): 402 [M+H]⁺.

Production Example 601-[4-(4-Amino-2-methylphenoxy)pyridin-2-yl]-3-(3-diethylaminopropyl)urea

To a solution of1-(3-diethylaminopropyl)-3-[4-(2-methyl-4-nitrophenoxy)pyridin-2-yl]urea(794 mg) in ethanol (50 ml) were added electrolytic iron powder (442mg), ammonium chloride (847 mg) and water (10 ml), followed by stirringat 90° C. for 1 hr. The reaction mixture was allowed to cool down toroom temperature, insoluble matter was removed by filtration, and thefiltrate was concentrated under reduced pressure. To the residue wasadded ethyl acetate (100 ml), washed with a saturated aqueous solutionof sodium hydrogencarbonate, and dried over anhydrous sodium sulfate.The solvent was removed and the resultant residue was purified by silicagel column chromatography (Fuji Silysia NH, eluent; hexane:ethylacetate=1:1 to 1:2, ethyl acetate, then ethyl acetate:methanol=20:1 to10:1) to provide the titled compound (110 mg, 15%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 0.93 (6H, t, J=7.2 Hz), 1.53 (2H, m),1.93 (3H, s), 2.38 (2H, m), 2.43 (4H, q, J=7.2 Hz), 3.12 (2H, m), 5.03(2H, m), 6.39 (1H, dd, J=2.4, 6.0 Hz), 6.44 (1H, dd, J=2.4, 8.4 Hz),6.49 (1H, d, J=2.4 Hz), 6.72 (2H, m), 7.97 (1H, d, J=6.0 Hz), 8.22 (1H,brs), 9.04 (1H, s).

ESI-MS (m/z): 372 [M+H]⁺.

Production Example 61 N-(1-Ethylpiperidin-4-yl)-N-methylamine

To a solution of 40% methylamine in methanol (1.26 g) were addedacetonitrile (150 ml), 1-ethyl-4-piperidone (2.0 ml) and acetic acid(0.932 ml), followed by addition of sodium triacetoxyborohydride (6.59g) and stirring for 1 hr. To the reaction mixture was added a saturatedaqueous solution of sodium hydrogencarbonate (20 ml), and the reactionmixture was concentrated under reduced pressure. The resultant residuewas suspended in methanol (20 ml), the solid was removed by filtrationand washed with methanol (20 ml). The filtrate was concentrated underreduced pressure, the resultant residue was suspended in tetrahydrofuran(50 ml). The solid was removed by filtration and washed withtetrahydrofuran (100 ml). The filtrate was concentrated under reducedpressure to provide a crude product of the titled compound as a paleyellow oil (3.33 g).

ESI-MS (m/z): 143 [M+H]⁺.

Example 1N-(3-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1.1-dicarboxamide

3-[4-(4-Amino-2-fluorophenoxy)pyridin-2-yl]-1-methyl-1-(1-methylpiperidin-4-yl)urea(40.8 mg) was dissolved in N,N-dimethylformamide (1.0 ml).1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (73 mg),triethylamine (0.0456 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(145 mg) were added under a nitrogen atmosphere at room temperature andstirred for 3.5 hr. Liquid-liquid separation was carried out afteraddition of ethyl acetate and water to the reaction mixture. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate and brine, and dried over anhydrous sodium sulfate.The solvent was removed and the resultant residue was purified by silicagel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=97:3) to provide the titled compound as whitepowder (26.3 mg, 42%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.80 (8H, m), 1.90-2.10 (2H, m),2.26 (3H, s), 2.80-2.94 (5H, m), 4.11 (1H, m), 6.57 (1H, dd, J=2.4, 5.6Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.63 (1H, d, J=2.4 Hz), 7.68(1H, dd, J=2.4, 12.0 Hz), 8.06 (1H, d, J=5.6 Hz), 8.65 (1H, m), 9.59(1H, brs).

ESI-MS (m/z): 579 [M+H]⁺.

Example 2N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) was added1-(2-dimethylaminoethyl)piperazine (59.0 mg), followed by stirring atroom temperature for 25 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, the residue was purified by silica gel columnchromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with diethyl ether:hexane=1:3 and dried under aeration toprovide the titled compound as white powder (31.7 mg, 69.6%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.68 (2H, m), 1.74 (2H, m), 2.26 (6H,m), 2.43-2.54 (8H, m), 3.45-3.53 (4H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz),6.91 (2H, m), 7.04 (2H, m), 7.24 (1H, s), 7.50 (2H, dd, J=4.8, 9.2 Hz),7.63 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=5.6 Hz), 8.19 (1H, m), 8.86 (1H,s), 9.20 (1H, s).

ESI-MS (m/z): 608 [M+H]⁺.

Example 3N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) was added1-methyl-4-(methylamino)piperidine (0.0436 ml), followed by stirring atroom temperature for 16 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethylacetate, then ethyl acetate:methanol=50:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with diethyl ether:hexane=1:3 and dried under aeration toprovide the titled compound as white powder (26.1 mg, 60.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.62-1.84 (8H, m), 2.07 (2H, m), 2.29(3H, s), 2.89 (3H, s), 2.92 (2H, m), 4.15 (1H, m), 6.50 (1H, dd, J=2.4,5.6 Hz), 6.91 (2H, m), 7.03 (2H, m), 7.21 (1H, s), 7.49 (2H, dd, J=4.8,9.2 Hz), 7.68 (1H, d, J=2.4 Hz), 8.07 (1H, d, J=5.6 Hz), 8.18 (1H, m),8.98 (1H, s), 9.19 (1H, s).

ESI-MS (m/z): 579 [M+H]⁺, 601 [M+Na]⁺.

Example 4N-(4-Fluorophenyl)-N′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) was added4-(pyrrolidin-1-yl)piperidine (46.3 mg), followed by stirring at roomtemperature for 16 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with diethyl ether:hexane=1:3 and dried under aeration toprovide the titled compound as white powder (36.9 mg, 81.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.57 (4H, m), 1.66 (2H, m), 1.75 (2H,m), 1.85 (4H, m), 1.98 (2H, m), 2.33 (1H, m), 2.67 (2H, m), 2.96 (2H,m), 4.04 (2H, m), 6.55 (1H, dd, J=2.0, 5.6 Hz), 6.92 (2H, m), 7.04 (2H,m), 7.25 (1H, m), 7.50 (2H, dd, J=4.8, 9.2 Hz), 7.61 (1H, d, J=2.0 Hz),8.06 (1H, d, J=5.6 Hz), 8.20 (1H, m), 8.78 (1H, s), 9.25 (1H, s).

ESI-MS (m/z): 605 [M+H]⁺.

Example 5N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

4-(Dimethylaminomethyl)piperidine-1-carboxylic acid[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (88 mg) was dissolved inN,N-dimethylformamide (2.5 ml).1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (101 mg),triethylamine (0.0633 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(201 mg) were added under a nitrogen atmosphere at room temperature,followed by stirring overnight. Liquid-liquid separation was carried outafter addition of ethyl acetate and water to the reaction mixture. Theorganic layer was washed with a 1N aqueous solution of sodium hydroxideand brine, and dried over anhydrous sodium sulfate. The solvent wasremoved and the resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=98:2). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of heptane to the resultant residue. The solid was collected byfiltration, and dried under aeration to provide the titled compound aswhite powder (39.8 mg, 30%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.15-1.30 (2H, m), 1.60-1.85 (7H, m),2.10-2.15 (2H, m), 2.64 (3H, s), 2.66 (3H, s), 2.87 (2H, m), 4.04 (2H,m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m),7.58 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.4, 12.0 Hz), 8.04 (1H, d,J=5.6 Hz), 8.73 (1H, brs), 9.57 (1H, brs).

ESI-MS (neg.) (m/z): 591[M−H]⁻.

Example 6N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclobutane-1,1-dicarboxamide

4-(Dimethylaminomethyl)piperidine-1-carboxylic acid[4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (114 mg) was dissolved inN,N-dimethylformamide (4.0 ml).1-(4-Fluorophenylcarbamoyl)cyclobutanecarboxylic acid (279 mg),triethylamine (0.164 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(520 mg) were added under a nitrogen atmosphere at room temperature andstirred overnight. Liquid-liquid separation was carried out afteraddition of ethyl acetate and water to the reaction mixture. The organiclayer was washed with 0.5N hydrochloric acid (4 times), water, asaturated aqueous solution of sodium hydrogencarbonate (3 times) andbrine in this order, and dried over anhydrous sodium sulfate. Thesolvent was removed and the resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=98:2). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of a mixture of diethyl ether and heptane (1:3) to theresultant residue. The solid was collected by filtration and dried underaeration to provide the titled compound as white powder (19.1 mg, 11%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10-1.25 (2H, m), 1.50-1.85 (3H, m),2.00-2.15 (4H, m), 2.21 (6H, s), 2.70-2.90 (6H, m), 4.00-4.10 (2H, m),6.54 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.20 (5H, m), 7.48-7.54 (2H, m), 7.57(1H, d, J=2.4 Hz), 7.73 (1H, dd, J=2.4, 12.0 Hz), 7.78 (1H, brs), 8.03(1H, d, J=5.6 Hz), 8.08 (1H, brs).

ESI-MS (m/z): 607 [M+H]⁺.

Example 7N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (130 mg) was added a solution of1-[2-(dimethylamino)ethyl]piperazine (123 mg) in N,N-dimethylformamide(2.5 ml) at room temperature, followed by stirring for 3.5 hr. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated aqueous solution of ammoniumchloride and brine in this order, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (42.3 mg, 36%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.78 (4H, m), 2.25 (6H, s),2.40-2.56 (8H, m), 3.46-3.54 (4H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz),7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.58 (1H, d, J=2.4 Hz), 7.69 (1H,dd, J=2.4, 12.0 Hz), 8.04 (1H, d, J=5.6 Hz), 8.49 (1H, brs), 9.53 (1H,brs).

ESI-MS (m/z): 608 [M+H]⁺.

Example 8N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) were added4-(dimethylaminomethyl)piperidine dihydrochloride (67.0 mg),triethylamine (0.0523 ml) and water (0.050 ml), followed by stirring atroom temperature for 10 hr. To the reaction mixture were addedtriethylamine (0.0523 ml) and water (0.050 ml), followed by furtherstirring at room temperature for 24 hr. The reaction mixture waspartitioned between ethyl acetate and a 1N aqueous solution of sodiumhydroxide. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed, and the residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added hexane, andthe precipitate was collected by filtration. This was washed with hexaneand dried under aeration to provide the titled compound as white powder(22.4 mg, 50.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10-1.20 (2H, m), 1.65-1.99 (7H, m),2.13 (2H, d, J=6.2 Hz), 2.21 (6H, s), 2.87 (2H, m), 4.06 (2H, m), 6.55(1H, m), 6.90 (2H, m), 7.03 (2H, m), 7.32 (1H, brs), 7.49 (2H, dd,J=5.0, 9.0 Hz), 7.62 (1H, s), 8.06 (1H, m), 8.15 (1H, m), 8.99 (1H, s),9.27 (1H, s).

ESI-MS (m/z): 593 [M+H]⁺.

Example 9N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) were added4-(azetidin-1-yl)piperidine dihydrochloride (79.9 mg), triethylamine(0.105 ml) and water (0.050 ml), followed by stirring at roomtemperature for 24 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, then ethylacetate:methanol=20:1). Fractions containing the target compound wereconcentrated. To the residue was added diethyl ether:hexane=1:3, and theprecipitate was collected by filtration. This was washed with hexane anddried under aeration to provide the titled compound as white powder(22.9 mg, 51.7%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.22-1.33 (2H, m), 1.64-1.83 (6H, m),2.06 (2H, m), 2.20 (1H, m), 3.03 (2H, m), 3.18 (4H, m), 3.89 (2H, m),6.54 (1H, dd, J=2.0, 6.0 Hz), 6.91 (2H, m), 7.03 (2H, m), 7.28 (1H, s),7.50 (2H, dd, J=4.8, 9.2 Hz), 7.61 (1H, d, J=2.0 Hz), 8.05 (1H, d, J=6.0Hz), 8.17 (1H, m), 8.85 (1H, s), 9.28 (1H, s).

ESI-MS (m/z): 591 [M+H]⁺.

Example 10

N-(4-Fluorophenyl)-N′-{3-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added4-(pyrrolidin-1-yl)piperidine (61.3 mg) at room temperature, followed bystirring overnight. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a saturated aqueoussolution of ammonium chloride and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (48.0 mg, 80%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-2.00 (12H, m), 2.20 (1H, m),2.50-2.64 (4H, m), 2.96 (2H, m), 3.92-4.04 (2H, m), 6.56 (1H, dd, J=2.4,5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.55 (1H, d, J=2.4 Hz),7.68 (1H, dd, J=2.4, 12.0 Hz), 8.04 (1H, d, J=5.6 Hz), 8.70 (1H, brs),9.48 (1H, brs).

ESI-MS (m/z): 605 [M+H]⁺.

Example 11N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added4-(azetidin-1-yl)piperidine dihydrochloride (85 mg) and triethylamine(0.112 ml) at room temperature, followed by stirring for 24 hr. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated aqueous solution of ammoniumchloride and brine in this order, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (34.6 mg, 59%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.16-1.34 (4H, m), 1.50-1.72 (4H, m),2.00-2.10 (2H, m), 2.19 (1H, m), 3.02 (2H, m), 3.10-3.24 (4H, m),3.80-3.90 (2H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m),7.40-7.50 (2H, m), 7.55 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.4, 12.0Hz), 8.04 (1H, d, J=5.6 Hz), 8.67 (1H, brs), 9.47 (1H, brs).

ESI-MS (m/z): 591[M+H]⁺.

Example 12N-(4-Fluorophenyl)-N′-(4-{[2-{[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0ml), and methyl(1-methylpiperidin-4-yl)amine (0.045 ml) was addedthereto, followed by stirring for 62 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate (20ml), water (20 ml) and brine (20 ml) in this order, and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure, and the resultant residue wassuspended in diethyl ether (2 ml) and hexane (4 ml). The solid wascollected by filtration and dried under aeration to provide the titledcompound as white powder (37.6 mg, 86.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.90 (8H, m), 2.08 (2H, m), 2.30(3H, s), 2.88 (3H, s), 2.93 (2H, m), 4.15 (1H, m), 6.54 (1H, dd, J=2.0,5.6 Hz), 6.90-7.14 (4H, m), 7.18 (1H, brs), 7.40-7.60 (4H, m), 7.64 (1H,d, J=2.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.95 (1H, brs), 9.09 (1H, brs).

ESI-MS (m/z): 583 [M+Na]⁺.

Example 13N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (82.9 mg),triethylamine (0.0782 ml) and water (0.100 ml) were added thereto inthis order, followed by stirring for 62 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (20 ml), water (20 ml) and brine (20 ml) in thisorder, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the resultant residue was purified by silicagel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure, and the resultant residue wassuspended in diethyl ether (2 ml) and hexane (4 ml). The solid wascollected by filtration and dried under aeration to provide the titledcompound as white powder (28.8 mg, 65.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.80 (8H, m), 2.06 (2H, m), 2.21(1H, m), 3.02 (2H, m), 3.19 (4H, m), 3.80-4.00 (2H, m), 6.53 (1H, dd,J=2.0, 5.6 Hz), 6.94-7.14 (5H, m), 7.40-7.66 (5H, m), 8.03 (1H, d, J=5.6Hz), 8.83 (1H, brs), 9.15 (1H, brs).

ESI-MS (m/z): 595 [M+Na]⁺.

Example 14N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) were addedN,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride(79.9 mg), triethylamine (0.105 ml) and water (0.050 ml), followed bystirring at room temperature for 12 hr. The reaction mixture waspartitioned between ethyl acetate and a 1N aqueous solution of sodiumhydroxide. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed, and the residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (30.8 mg, 64.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.31 (2H, m), 1.50-1.80 (6H, m), 2.14(6H, s), 2.32 (1H, m), 2.90 (3H, m), 3.05 (2H, m), 3.53 (2H, m), 3.89(2H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.92 (2H, m), 7.04 (2H, m), 7.23(1H, s), 7.50 (2H, dd, J=4.8, 9.2 Hz), 7.61 (1H, d, J=2.4 Hz), 8.06 (1H,d, J=5.6 Hz), 8.19 (1H, m), 8.77 (1H, s), 9.25 (1H, s).

ESI-MS (m/z): 634 [M+H]⁺, 656 [M+Na]⁺.

Example 15N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Method A

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) was added1-methyl-4-(piperidin-4-yl)piperazine (68.7 mg), followed by stirring atroom temperature for 12 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, ethylacetate:methanol=20:1, then 10:1). Fractions containing the targetcompound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (34.6 mg, 72.8%).

The titled compound could be synthesized by the following method.

Method B

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(1.137 g) and sodium hydrogencarbonate (1.35 g) were dissolved in ethylacetate (20 ml) and water (10 ml), and phenyl chloroformate (0.841 ml)was added at room temperature, followed by stirring for 30 min. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (twice) and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (15 ml),and 1-methyl-4-(piperidin-4-yl)piperazine (1.23 g) was added at roomtemperature, followed by stirring overnight. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a saturated aqueous solution of ammonium chloride, water andbrine in this order, and dried over anhydrous sodium sulfate. Thesolvent was removed, and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:4,ethyl acetate, ethyl acetate:methanol=95:5). Fractions containing thetarget compound were concentrated. To the resultant residue (836 mg) wasadded ethyl acetate:tert-butyl methyl ether=1:2 to suspend a solid. Thesolid was collected by filtration and washed with tert-butyl methylether. This was dried under aeration to provide the titled compound aswhite powder (584 mg, 34.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (2H, m), 1.68 (2H, m), 1.75 (2H,m), 1.90 (2H, m), 2.32 (3H, s), 2.39-2.71 (9H, m), 2.90 (2H, m), 4.11(2H, m), 6.55 (1H, dd, J=2.0, 5.6 Hz), 6.92 (2H, m), 7.04 (2H, m), 7.26(1H, covered by CDCl₃), 7.50 (2H, dd, J=4.8, 9.2 Hz), 7.62 (1H, d, J=2.0Hz), 8.06 (1H, d, J=5.6 Hz), 8.20 (1H, m), 8.84 (1H, s), 9.20 (1H, s).

ESI-MS (m/z): 634 [M+H]⁺, 656 [M+Na]⁺.

Example 16N-(2-Fluoro-4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) was added1-(N-methylpiperidin-4-yl)piperazine (68.7 mg), followed by stirring atroom temperature for 12 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, ethylacetate:methanol=20:1 then 10:1). Fractions containing the targetcompound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (30.1 mg, 63.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.59-1.76 (8H, m), 1.96 (2H, m), 2.28(4H, m), 2.57 (4H, m), 2.92 (2H, m), 3.50 (4H, m), 6.55 (1H, dd, J=2.0,5.6 Hz), 6.91 (2H, m), 7.04 (2H, m), 7.24 (1H, s), 7.50 (2H, dd, J=4.8,9.2 Hz), 7.62 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=5.6 Hz), 8.19 (1H, m),8.88 (1H, s), 9.20 (1H, s).

ESI-MS (m/z): 634 [M+H]⁺, 656 [M+Na]⁺.

Example 17N-(2-Fluoro-4-{[2-{[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) were added1-(1-methylazetidin-3-yl)piperazine trihydrochloride (79.4 mg),triethylamine (0.125 ml) and water (0.10 ml), followed by stirring atroom temperature for 6 hr. To the reaction mixture were added1-(1-methylazetidin-3-yl)piperazine trihydrochloride (19.9 mg) andtriethylamine (0.032 ml), followed by stirring at room temperature for 2hr. The reaction mixture was partitioned between ethyl acetate and a 1Naqueous solution of sodium hydroxide. The organic layer was washed withbrine, and dried over anhydrous sodium sulfate. The solvent was removed,and the residue was purified by silica gel column chromatography (FujiSilysia NH, ethyl acetate, ethyl acetate:methanol=20:1 then 10:1).Fractions containing the target compound were concentrated. To theresidue was added diethyl ether:hexane=1:3, and the precipitate wascollected by filtration. This was washed with hexane and dried underaeration to provide the titled compound as white powder (19.7 mg,43.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.67 (2H, m), 1.73 (2H, m), 2.06 (3H,s), 2.31-2.36 (6H, m), 2.93 (3H, m), 3.51 (4H, m), 6.55 (1H, dd, J=2.0,5.6 Hz), 6.88-6.93 (2H, m), 7.03 (2H, m), 7.25 (1H, s), 7.49 (2H, dd,J=4.8, 9.2 Hz), 7.62 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=5.6 Hz), 8.19(1H, m), 8.93 (1H, s), 9.19 (1H, s).

ESI-MS (m/z): 606 [M+H]⁺, 628 [M+Na]⁺.

Example 18N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) were addedN,N-dimethyl-N-(piperidin-4-yl)amine dihydrochloride (79.4 mg),triethylamine (0.157 ml) and water (0.10 ml), followed by stirring atroom temperature for 10 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, ethylacetate:methanol=20:1, then 10:1). Fractions containing the targetcompound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (30.6 mg, 70.5%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43-1.53 (2H, m), 1.66-1.77 (4H, m),1.89 (2H, m), 2.30 (6H, m), 2.37 (1H, m), 2.91 (2H, m), 4.11 (2H, m),6.56 (1H, dd, J=2.0, 5.6 Hz), 6.91-6.95 (2H, m), 7.05 (2H, m), 7.30 (1H,s), 7.51 (2H, dd, J=4.8, 9.2 Hz), 7.64 (1H, d, J=2.0 Hz), 8.08 (1H, d,J=5.6 Hz), 8.19 (1H, m), 8.89 (1H, s), 9.24 (1H, s).

ESI-MS (m/z): 579 [M+H]⁺, 601 [M+Na]⁺.

Example 19N-(3-Fluoro-4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added1-(1-methylpiperidin-4-yl)piperazine (73.3 mg) at room temperature,followed by stirring overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (56.4 mg, 89%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.80 (8H, m), 1.93 (2H, m),2.20-2.34 (4H, m), 2.50-2.60 (4H, m), 2.84-2.96 (2H, m), 3.40-3.56 (4H,m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m),7.56 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.4, 12.0 Hz), 8.05 (1H, d,J=5.6 Hz), 8.60 (1H, brs), 9.54 (1H, brs).

ESI-MS (m/z): 634 [M+H]⁺.

Example 20N-(3-Fluoro-4-{[2-({[-4-(4-methylpiperazin-1-yl)piperidin-1-yl]-carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added1-methyl-4-(piperidin-4-yl)piperazine (73.3 mg) at room temperature,followed by stirring overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolvent was removed under reduced pressure. The solid residue was driedunder reduced pressure to provide the titled compound as white powder(60.1 mg, 95%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.00 (9H, m), 2.29 (3H, s),2.35-2.70 (8H, m), 2.88 (2H, m), 4.00-4.10 (2H, m), 6.56 (1H, dd, J=2.4,5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.56 (1H, d, J=2.4 Hz),7.68 (1H, dd, J=2.4, 12.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.63 (1H, brs),9.54 (1H, brs).

ESI-MS (m/z): 656 [M+Na]⁺.

Example 21N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (116 mg) andtriethylamine (0.168 ml) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with a saturated aqueoussolution of ammonium chloride and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolvent was removed under reduced pressure. The solid residue was driedunder reduced pressure to provide the titled compound as white powder(57.5 mg, 91%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.20-1.80 (8H, m), 2.11 (6H, s), 2.25(1H, m), 2.74-2.90 (3H, m), 3.04 (2H, m), 3.40-3.50 (2H, m), 3.80-3.90(2H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H,m), 7.55 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.4, 12.0 Hz), 8.04 (1H, d,J=5.6 Hz), 8.66 (1H, brs), 9.48 (1H, brs).

ESI-MS (m/z): 634 [M+H]⁺.

Example 22N-(3-Fluoro-4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added1-(1-methylazetidin-3-yl)piperazine trihydrochloride (106 mg) andtriethylamine (0.167 ml) at room temperature, followed by stirring for25 hr. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous solution ofammonium chloride and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (20.2 mg, 33%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.25-2.34 (4H, m),2.35 (3H, s), 2.85-3.00 (3H, m), 3.45-3.55 (6H, m), 6.56 (1H, dd, J=2.4,5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.55 (1H, d, J=2.4 Hz),7.68 (1H, dd, J=2.4, 12.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.57 (1H, brs),9.57 (1H, brs).

ESI-MS (m/z): 606 [M+H]⁺.

Example 23N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) were added4-dimethylaminopiperidine dihydrochloride (80.5 mg) and triethylamine(0.112 ml) at room temperature, followed by stirring overnight. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated aqueous solution of ammoniumchloride and brine in this order, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (52.1 mg, 90%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.76 (6H, m), 1.80-1.90 (2H, m),2.28 (6H, s), 2.35 (1H, m), 2.89 (2H, m), 4.02-4.12 (2H, m), 6.55 (1H,dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50 (2H, m), 7.57 (1H, d,J=2.4 Hz), 7.69 (1H, dd, J=2.4, 12.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.54(1H, brs), 9.52 (1H, brs).

ESI-MS (m/z): 579 [M+H]⁺.

Example 24N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (66 mg) in N,N-dimethylformamide (1.0 ml) was added(3S)-3-dimethylaminopyrrolidine (0.0508 ml) at room temperature,followed by stirring for 6 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=98:2). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolvent was removed under reduced pressure. The solid residue was driedunder reduced pressure to provide the titled compound as white powder(45.6 mg, 81%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.75 (4H, m), 1.87 (1H, m), 2.16(1H, m), 2.27 (6H, s), 2.75 (1H, m), 3.21 (1H, m), 3.39 (1H, m), 3.64(1H, m), 3.71 (1H, m), 6.58 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m),7.40-7.50 (2H, m), 7.63 (1H, d, J=2.4 Hz), 7.69 (1H, dd, J=2.4, 12.0Hz), 8.05 (1H, d, J=5.6 Hz), 8.61 (1H, brs), 9.50 (1H, brs).

ESI-MS (m/z): 587 [M+Na]⁺.

Example 25N-(4-{[2-({[{1-[2-(Dimethylamino)ethyl]piperidin-4-yl}(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) was addedN-[1-(2-dimethylaminoethyl)piperidin-4-yl]-N-methylamine (69.5 mg),followed by stirring at room temperature for 22 hr. The reaction mixturewas partitioned between ethyl acetate and a 1N aqueous solution ofsodium hydroxide. The organic layer was washed with brine, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (31.4 mg, 65.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.83 (8H, m), 2.05-2.11 (2H, m),2.24 (6H, s), 2.39-2.49 (4H, m), 2.88 (3H, s), 3.00 (2H, m), 4.13 (1H,m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.91 (2H, m), 7.03 (2H, m), 7.21 (1H,s), 7.49 (2H, dd, J=4.8, 9.2 Hz), 7.68 (1H, d, J=2.4 Hz), 8.07 (1H, d,J=5.6 Hz), 8.18 (1H, m), 8.97 (1H, s), 9.21 (1H, s).

ESI-MS (m/z): 636 [M+H]⁺.

Example 26N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) were added4-(azetidin-1-ylmethyl)piperidine dihydrochloride (69 mg) andtriethylamine (0.085 ml) at room temperature, followed by stirring for 3hr. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous solution ofammonium chloride and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2).Fractions containing the titled compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (42.0 mg, 92%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.05-1.20 (2H, m), 1.45-1.80 (7H, m),2.07 (2H, m), 2.28 (2H, d, J=6.8 Hz), 2.84 (2H, m), 3.10-3.25 (4H, m),4.02 (2H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m), 7.40-7.50(2H, m), 7.58 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.4, 12.0 Hz), 8.04(1H, d, J=5.6 Hz), 8.55 (1H, brs), 9.49 (1H, brs).

ESI-MS (m/z): 605 [M+H]⁺.

Example 27 N-(4-{[2-({f[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0ml), and 4-(azetidin-1-ylmethyl)piperidine dihydrochloride (70.2 mg),triethylamine (0.0862 ml) and water (0.100 ml) were added thereto inthis order, followed by stirring for 62 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of ammonium chloride (20 ml). The organic layer was washed witha saturated aqueous solution of ammonium chloride (20 ml), water (20 ml)and brine (20 ml) in this order, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure, and the resultant residue was suspended in diethyl ether (2ml) and hexane (4 ml). The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (35.8 mg,78.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.06-1.30 (2H, m), 1.43-1.73 (5H, m),1.75 (2H, m), 2.08 (2H, m), 2.31 (2H, m), 2.84 (2H, m), 3.20 (4H, m),4.03 (2H, m), 6.53 (1H, dd, J=2.4, 6.0 Hz), 6.95-7.12 (4H, m), 7.43-7.65(6H, m), 8.03 (1H, d, J=6.0 Hz), 8.87 (1H, brs), 9.14 (1H, brs).

ESI-MS (m/z): 587 [M+H]⁺.

Example 28N-(4-{[2-({[4-(2-Azetidin-1-ylethyl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[4-(4-{[1-(4-Fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) was dissolved in N,N-dimethylformamide (1.0ml), and 1-[2-(azetidin-1-yl)ethyl]piperazine trihydrochloride (64.6mg), triethylamine (0.129 ml) and water (0.100 ml) were added thereto inthis order, followed by stirring for 20 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of ammonium chloride (20 ml). The organic layer was washed witha saturated aqueous solution of ammonium chloride (20 ml), water (20 ml)and brine (20 ml) in this order, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=9:1).Fractions containing the target compound were concentrated under reducedpressure, and the resultant residue was suspended in diethyl ether (2ml) and hexane (4 ml). The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (23.8 mg,51.2%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.90 (4H, m), 2.05-2.17 (2H, m),2.33-2.42 (2H, m), 2.46 (4H, m), 2.50-2.65 (2H, m), 3.25 (4H, m), 3.49(4H, m), 6.54 (1H, dd, J=2.4, 6.0 Hz), 6.94-7.16 (4H, m), 7.42-7.68 (6H,m), 8.03 (1H, d, J=6.0 Hz), 8.90 (1H, brs), 9.08 (1H, brs).

ESI-MS (m/z): 602 [M+H]⁺.

Example 29N-(4-Fluorophenyl)-N′-(4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]-carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

4-(Pyrrolidin-1-ylmethyl)piperidine-1-carboxylic acid[4-(4-aminophenoxy)pyridin-2-yl]amide (125 mg) was dissolved inN,N-dimethylformamide (2 ml), and1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (176 mg),triethylamine (0.11 ml) and(1H-1,2,3-benzotriazol-1-yloxy)[tri(dimethylamino)]phosphoniumhexafluorophosphate (349 mg) were added thereto in this order at roomtemperature, followed by stirring for 1 hr. Liquid-liquid separation wascarried out after addition of ethyl acetate and a saturated aqueoussolution of sodium hydrogencarbonate to the reaction mixture. Theorganic layer was washed with brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; heptane:ethyl acetate=1:5, then ethyl acetate). Thesolvent was concentrated under reduced pressure, and the resultantresidue was suspended in diethyl ether (4 ml) and hexane (4 ml). Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (121.2 mg, 63.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10-1.35 (2H, m), 1.50-1.75 (5H, m),1.75-1.90 (6H, m), 2.35 (2H, m), 2.45-2.58 (4H, m), 2.86 (2H, m), 4.05(2H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.90-7.14 (4H, m), 7.44-7.62 (6H,m), 8.03 (1H, d, J=5.6 Hz), 8.87 (1H, brs), 9.18 (1H, brs).

ESI-MS (m/z): 601 [M+H]⁺.

Example 30N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) was added a solution of1-[2-(dimethylamino)ethyl]piperazine (48.6 mg) in N,N-dimethylformamide(1.0 ml) at room temperature, followed by stirring for 5 hr. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated aqueous solution of ammoniumchloride and brine in this order, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (34.7 mg, 76%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.74 (4H, m), 2.27 (6H, s),2.40-2.56 (8H, m), 3.46-3.56 (4H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz),7.00-7.10 (4H, m), 7.17 (1H, brs), 7.44-7.62 (5H, m), 8.03 (1H, d, J=5.6Hz), 8.85 (1H, brs), 9.01 (1H, brs).

ESI-MS (m/z): 590 [M+H]⁺.

Example 31N-(4-Fluorophenyl)-N′-(4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added1-(1-methylpiperidin-4-yl)piperazine (56.7 mg) at room temperature,followed by stirring for 5 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolvent was removed under reduced pressure. The solid residue was driedunder reduced pressure to provide the titled compound as white powder(40.1 mg, 84%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.82 (8H, m), 1.95 (2H, m),2.24-2.34 (4H, m), 2.54-2.60 (4H, m), 2.92 (2H, m), 3.44-3.54 (4H, m),6.53 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.10 (4H, m), 7.17 (1H, brs),7.44-7.62 (5H, m), 8.04 (1H, d, J=5.6 Hz), 8.85 (1H, brs), 9.01 (1H,brs).

ESI-MS (m/z): 616 [M+H]⁺.

Example 32N-(4-Fluorophenyl)-N′-(4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added1-methyl-4-(piperidin-4-yl)piperazine (56.7 mg) at room temperature,followed by stirring overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolvent was removed under reduced pressure. The solid residue was driedunder reduced pressure to provide the titled compound as white powder(37.7 mg, 79%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.94 (9H, m), 2.28 (3H, s),2.30-2.70 (8H, m), 2.88 (2H, m), 4.02-4.14 (2H, m), 6.54 (1H, dd, J=2.4,5.6 Hz), 7.00-7.10 (4H, m), 7.23 (1H, brs), 7.45-7.60 (5H, m), 8.03 (1H,d, J=5.6 Hz), 8.89 (1H, brs), 9.12 (1H, brs).

ESI-MS (m/z): 616 [M+H]⁺.

Example 33N-(3-Fluoro-4-{[6-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyrimidin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamicacid phenyl ester (40 mg) was dissolved in N,N-dimethylformamide (1.0ml), and 1-methyl-4-(methylamino)piperidine (0.045 ml) was addedthereto, followed by stirring for 3 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of ammonium chloride (20 ml). The organic layer was washed witha saturated aqueous solution of ammonium chloride (20 ml), water (20 ml)and brine (20 ml) in this order, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure, and the resultant residue was suspended in diethyl ether (2ml) and hexane (4 ml). The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (33.7 mg,79.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.75 (6H, m), 1.75-1.90 (2H, m),2.06-2.17 (2H, m), 2.30 (3H, s), 2.92 (3H, s), 2.96 (2H, m), 4.10-4.25(1H, m), 7.05 (2H, m), 7.12-7.24 (2H, m), 7.31 (1H, brs), 7.40-7.50 (2H,m), 7.65 (1H, m), 7.68 (1H, dd, J=2.0, 12.0 Hz), 8.34 (1H, m), 8.49 (1H,brs), 9.48 (1H, brs).

ESI-MS (m/z): 602 [M+Na]⁺.

Example 34N-{4-[(6-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyrimidin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamicacid phenyl ester (35.5 mg) was dissolved in N,N-dimethylformamide (1.0ml), and 4-(azetidin-1-yl)piperidine dihydrochloride (21 mg),triethylamine (0.0198 ml) and water (0.10 ml) were added thereto in thisorder, followed by stirring for 21 hr. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of ammonium chloride (20 ml). The organic layer was washed witha saturated aqueous solution of ammonium chloride (20 ml), water (20 ml)and brine (20 ml) in this order, and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure, and the resultant residue was suspended in diethyl ether (2ml) and hexane (4 ml). The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (26.5 mg,68.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.15-1.42 (4H, m), 1.45-1.90 (4H, m),2.09 (2H, m), 2.28 (1H, m), 3.11 (2H, m), 3.16-3.35 (4H, m), 3.80-3.90(2H, m), 7.00-7.12 (2H, m), 7.12-7.26 (2H, m), 7.37 (1H, brs), 7.41-7.52(2H, m), 7.59 (1H, s), 7.63-7.76 (1H, m), 8.34 (1H, m), 8.53 (1H, brs),9.42 (1H, brs).

ESI-MS (m/z): 614 [M+Na]⁺.

Example 35N-[3-Fluoro-4-({6-{(morpholin-4-ylcarbonyl)amino}pyrimidin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

[6-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyrimidin-4-yl]carbamicacid phenyl ester (40 mg) was dissolved in N,N-dimethylformamide (1.0ml), and morpholine (0.045 ml) was added thereto, followed by stirringfor 26 hr. The reaction mixture was partitioned between ethyl acetate(50 ml) and a saturated aqueous solution of ammonium chloride (20 ml).The organic layer was washed with a saturated aqueous solution ofammonium chloride (20 ml), water (20 ml) and brine (20 ml) in thisorder, and dried over anhydrous sodium sulfate. The solvent was removedunder reduced pressure, and the resultant residue was purified by silicagel column chromatography (Fuji Silysia NH, eluent; heptane:ethylacetate=1:5, then ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure, and the resultantresidue was suspended in diethyl ether (2 ml) and hexane (4 ml). Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (18.3 mg, 82.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.54-1.67 (2H, m), 1.68-1.78 (2H, m),3.52 (4H, m), 3.75 (4H, m), 7.06 (2H, m), 7.12-7.25 (2H, m), 7.31-7.38(1H, m), 7.45 (2H, m), 7.61 (1H, s), 7.69 (1H, dd, J=2.0, 11.2 Hz), 8.35(1H, s), 8.42 (1H, brs), 9.52 (1H, brs).

ESI-MS (m/z): 561 [M+Na]⁺.

Example 36N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added(3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followedby stirring for 4 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a saturated aqueoussolution of ammonium chloride and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=98:2). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (21.8 mg, 51%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.75 (4H, m), 1.87 (1H, m), 2.16(1H, m), 2.27 (6H, s), 2.75 (1H, m), 3.21 (1H, m), 3.39 (1H, m), 3.64(1H, m), 3.71 (1H, m), 6.58 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.30 (5H, m),7.40-7.50 (2H, m), 7.63 (1H, d, J=2.4 Hz), 7.69 (1H, dd, J=2.4, 12.0Hz), 8.05 (1H, d, J=5.6 Hz), 8.61 (1H, brs), 9.50 (1H, brs).

ESI-MS (m/z): 587 [M+Na]⁺.

Example 37N-(4-{[2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) was added4-(azetidin-1-ylmethyl)piperidine dihydrochloride (85.2 mg), followed bystirring at room temperature for 16 hr. The reaction mixture waspartitioned between ethyl acetate and a 1N aqueous solution of sodiumhydroxide. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed, and the residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (21.9 mg, 48.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.16 (2H, m), 1.66 (3H, m), 1.75 (4H,m), 2.08 (2H, m), 2.31 (2H, d, J=6.8 Hz), 2.85 (2H, m), 3.20 (4H, m),4.04 (2H, m), 6.54 (1H, dd, J=2.4, 6.0 Hz), 6.91 (2H, m), 7.04 (2H, m),7.24 (1H, brs), 7.50 (2H, dd, J=5.0, 9.0 Hz), 7.63 (1H, d, J=2.4 Hz),8.06 (1H, d, J=6.0 Hz), 8.19 (1H, m), 8.80 (1H, s), 9.23 (1H, s).

ESI-MS (m/z): 605 [M+H]⁺.

Example 38N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) were addedN,N-dimethyl-N-[1-(piperidin-4-yl)azetidin-3-yl]amine trihydrochloride(90.5 mg), triethylamine (0.129 ml) and water (0.10 ml), followed bystirring at room temperature for 12 hr. The reaction mixture waspartitioned between ethyl acetate and a 1N aqueous solution of sodiumhydroxide. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed, and the residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (11.8 mg, 24.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.31 (2H, m), 1.64-1.76 (6H, m), 2.14(6H, s), 2.30 (1H, m), 2.90 (3H, m), 3.03 (2H, m), 3.52 (2H, m), 3.88(2H, m), 6.53 (1H, dd, J=2.2, 6.0 Hz), 7.06 (2H, m), 7.08 (2H, d, J=8.8Hz), 7.24 (1H, m), 7.49 (2H, dd, J=4.6, 9.0 Hz), 7.55 (3H, m), 8.02 (1H,d, J=6.0 Hz), 8.81 (1H, m), 9.10 (1H, m).

ESI-MS (m/z): 638 [M+Na]⁺.

Example 39N-(4-{[2-({[{1-[2-(Dimethylamino)ethyl]piperidin-4-yl}(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (2.0 ml) was addedN-[1-(2-dimethylaminoethyl)piperidin-4-yl]-N-methylamine (69.5 mg),followed by stirring at room temperature for 12 hr. The reaction mixturewas partitioned between ethyl acetate and a 1N aqueous solution ofsodium hydroxide. The organic layer was washed with brine, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue was added diethylether:hexane=1:3, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (15.8 mg, 33.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.57-1.83 (8H, m), 2.00 (2H, m), 2.23(6H, s), 2.36-2.45 (4H, m), 2.87 (3H, s), 2.92 (2H, m), 4.08 (1H, m),6.57 (1H, dd, J=2.4, 5.6 Hz), 7.02 (2H, m), 7.06 (2H, d, J=9.0 Hz), 7.22(1H, brs), 7.49 (2H, dd, J=4.8, 9.2 Hz), 7.54 (2H, d, J=9.0 Hz), 7.62(1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 9.06 (1H, s), 9.32 (1H, s).

ESI-MS (m/z): 640 [M+Na]⁺.

Example 40N-(4-Fluorophenyl)-N′-(2-fluoro-4-{[2-({[4-(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(41.0 mg) in N,N-dimethylformamide (2.0 ml) were added4-(pyrrolidin-1-ylmethyl)piperidine dihydrochloride (74.2 mg),triethylamine (0.0857 ml) and water (0.20 ml), followed by stirring atroom temperature for 13 hr. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, heptane:ethyl acetate=1:2, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated. To the residue were added diethylether and hexane, and the precipitate was collected by filtration. Thiswas washed with hexane and dried under aeration to provide the titledcompound as white powder (10.5 mg, 28%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.21 (2H, m), 1.65-1.92 (11H, m), 2.46(2H, m), 2.66 (4H, m), 2.88 (2H, m), 4.08 (2H, m), 6.55 (1H, dd, J=2.4,5.6 Hz), 6.91 (2H, m), 7.04 (2H, m), 7.29 (1H, brs), 7.50 (2H, dd,J=4.6, 9.0 Hz), 7.62 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=5.6 Hz), 8.18(1H, m), 8.85 (1H, s), 9.25 (1H, s).

ESI-MS (m/z): 619 [M+H]⁺.

Example 41N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added(3S)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followedby stirring for 3 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a saturated aqueoussolution of ammonium chloride and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=98:2). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:3 to the resultant residue. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (23.0 mg, 54%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.75 (4H, m), 1.89 (1H, m), 2.17(1H, m), 2.29 (6H, s), 2.75 (1H, m), 3.23 (1H, m), 3.41 (1H, m), 3.65(1H, m), 3.73 (1H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.99-7.14 (5H, m),7.44-7.58 (4H, m), 7.66 (1H, d, J=2.4 Hz), 8.03 (1H, d, J=5.6 Hz), 8.81(1H, brs), 9.01 (1H, brs).

ESI-MS (m/z): 547 [M+H]⁺.

Example 42N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (50 mg) in N,N-dimethylformamide (1.0 ml) was added(3R)-3-dimethylaminopyrrolidine (0.050 ml) at room temperature, followedby stirring for 3 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a saturated aqueoussolution of ammonium chloride and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=98:2). Fractions containing the target compound wereconcentrated under reduced pressure. A solid was precipitated byaddition of ethyl acetate:heptane=1:5 to the resultant residue. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (16.3 mg, 39%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.75 (4H, m), 1.89 (1H, m), 2.17(1H, m), 2.29 (6H, s), 2.75 (1H, m), 3.23 (1H, m), 3.41 (1H, m), 3.65(1H, m), 3.73 (1H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.99-7.14 (5H, m),7.44-7.58 (4H, m), 7.66 (1H, d, J=2.4 Hz), 8.03 (1H, d, J=5.6 Hz), 8.81(1H, brs), 9.01 (1H, brs).

ESI-MS (m/z): 547 [M+H]⁺.

Example 43N-[2-Chloro-4-({2-[({[3-(diethylamino)propyl]amino}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-[(4-amino-3-chlorophenoxy)pyridin-2-yl]-3-(3-dimethylaminopropyl)urea(67.0 mg) in N,N-dimethylformamide (2.0 ml) were added1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (115 mg),benzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphate (227mg) and triethylamine (0.0681 ml), followed by stirring at roomtemperature for 2 days. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, then ethylacetate:methanol=20:1). Fractions containing the target compound wereconcentrated. The residue was purified by LC-MS. Fractions containingthe target compound were concentrated, the residue was partitionedbetween ethyl acetate and saturated sodium hydrogencarbonate. Theorganic layer was washed with brine, and dried over anhydrous sodiumsulfate. The solvent was removed to provide the titled compound ascolorless powder (9.0 mg, 8.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.10 (6H, t, J=7.0 Hz), 1.68-1.83 (6H,m), 2.70 (6H, m), 3.36 (2H, m), 6.31 (1H, m), 6.49 (1H, m), 7.04 (3H,m), 7.17 (1H, m), 7.52 (2H, dd, J=4.4, 8.4 Hz), 7.90 (1H, m), 8.02 (1H,d, J=6.0 Hz), 8.31 (1H, d, J=8.8 Hz), 9.32 (3H, m).

ESI-MS (neg.) (m/z): 595 [M−H]⁻.

Example 44N-(4-{[2-({[[3-(Diethylamino)propyl](methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-3-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-[(4-amino-2-fluorophenoxy)pyridin-2-yl]-3-(3-dimethylaminopropyl)-3-methylurea(50.0 mg) in N,N-dimethylformamide (2.0 ml) were added1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (85.7 mg),benzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphate (170mg) and triethylamine (0.0510 ml), followed by stirring at roomtemperature for 2 days. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2, ethylacetate, then ethyl acetate:methanol=20:1). Fractions containing thetarget compound were concentrated to provide the titled compound ascolorless powder (30.0 mg, 39.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.05 (6H, t, J=7.2 Hz), 1.76 (4H, m),2.45 (2H, m), 2.64 (6H, m), 2.80 (3H, s), 3.37 (2H, m), 6.57 (1H, dd,J=2.4, 5.6 Hz), 6.98 (2H, m), 7.05 (1H, m), 7.19 (2H, m), 7.44-7.51 (3H,m), 7.63 (1H, dd, J=2.2, 8.2 Hz), 8.07 (1H, d, J=2.4 Hz), 9.46 (1H, s),9.62 (1H, s).

ESI-MS (neg.) (m/z): 593 [M−H]⁻.

Example 45N-[4-({2-[({[3-(Diethylamino)propyl]amino}carbonyl)amino]pyridin-4-yl}oxy)-3-methylphenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-[(4-amino-2-methylphenoxy)pyridin-2-yl]-3-(3-dimethylaminopropyl)urea(50.0 mg) in N,N-dimethylformamide (2.0 ml) were added1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (90.4 mg),benzotriazol-1-yltris(dimethylamino)phosphonium hexafluorophosphate (179mg) and triethylamine (0.0538 ml), followed by stirring at roomtemperature for 2 days. The reaction mixture was partitioned betweenethyl acetate and a 1N aqueous solution of sodium hydroxide. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, ethyl acetate, then ethylacetate:methanol=20:1). Fractions containing the target compound wereconcentrated. The residue was purified by LC-MS. Fractions containingthe target compound were concentrated, and the residue was partitionedbetween ethyl acetate and saturated sodium hydrogencarbonate. Theorganic layer was washed with brine, and dried over anhydrous sodiumsulfate. The solvent was removed to provide the titled compound ascolorless powder (22.6 mg, 29.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.05 (6H, t, J=7.0 Hz), 1.63-1.79 (6H,m), 2.13 (3H, s), 2.56-2.63 (6H, m), 3.33 (2H, m), 6.14 (1H, m), 6.43(1H, dd, J=2.4, 6.0 Hz), 6.96 (1H, d, J=8.8 Hz), 7.03 (2H, m), 7.40 (1H,dd, J=2.4, 8.8 Hz), 7.47-7.51 (3H, m), 7.81 (1H, m), 7.95 (1H, d, J=6.0Hz), 9.12 (1H, brs), 9.25 (1H, brs), 9.28 (1H, brs).

ESI-MS (m/z): 577 [M+H]⁺.

Example 46N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(60.8 mg) in N,N-dimethylformamide (1.0 ml) was added(3S)-(−)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring atroom temperature for 7 hr. The reaction mixture was partitioned betweenethyl acetate and 1N sodium hydroxide. The organic layer was washed withbrine, and dried over anhydrous sodium sulfate. The solvent was removed,and the residue was purified by silica gel column chromatography (FujiSilysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractionscontaining the target compound were concentrated. To the residue wasadded diethyl ether:hexane=1:2, and the precipitated solid was collectedby filtration. This was dried under aeration to provide the titledcompound as white powder (18.5 mg, 35.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 1.86 (1H, m), 2.17(1H, m), 2.27 (6H, s), 2.74 (1H, m), 3.21 (1H, m), 3.41 (1H, m), 3.65(1H, m), 3.72 (1H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.91 (2H, d, J=9.2Hz), 7.03 (2H, m), 7.07 (1H, brs), 7.50 (2H, m), 7.68 (1H, d, J=2.4 Hz),8.06 (1H, d, J=5.6 Hz), 8.18 (1H, m), 8.88 (1H, m), 9.27 (1H, s).

ESI-MS (m/z): 587 [M+Na]⁺.

Example 47N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(60.8 mg) in N,N-dimethylformamide (1.0 ml) was added(3R)-(+)-3-dimethylaminopyrrolidine (41.7 mg), followed by stirring atroom temperature for 7 hr. The reaction mixture was partitioned betweenethyl acetate and 1N sodium hydroxide. The organic layer was washed withbrine, and dried over anhydrous sodium sulfate. The solvent was removed,and the residue was purified by silica gel column chromatography (FujiSilysia NH, ethyl acetate, then ethyl acetate:methanol=20:1). Fractionscontaining the target compound were concentrated. To the residue wasadded diethyl ether:hexane=1:2, and the precipitated solid was collectedby filtration. This was dried under aeration to provide the titledcompound as white powder (18.3 mg). This was purified again by silicagel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=1:2,ethyl acetate, then ethyl acetate:methanol=20:1). Fractions containingthe target compound were concentrated. To the residue was added diethylether:hexane=1:2, and the precipitated solid was collected byfiltration. This was dried under aeration to provide the titled compoundas white powder (12.3 mg, 23.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 1.87 (1H, m), 2.17(1H, m), 2.27 (6H, s), 2.74 (1H, m), 3.21 (1H, m), 3.41 (1H, m), 3.65(1H, m), 3.72 (1H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.91 (2H, m), 7.03(2H, m), 7.09 (1H, brs), 7.50 (2H, m), 7.69 (1H, d, J=2.4 Hz), 8.06 (1H,d, J=5.6 Hz), 8.18 (1H, m), 8.87 (1H, m), 9.26 (1H, s).

ESI-MS (m/z): 587 [M+Na]⁺.

Example 48N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were added aniline (0.015ml), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 5 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (24.5 mg, 53%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.85 (8H, m), 2.00-2.15 (2H, m),2.30 (3H, s), 2.85-3.00 (5H, m), 4.17 (1H, m), 6.54 (1H, dd, J=2.4, 5.6Hz), 6.90-6.93 (2H, m), 7.15 (1H, m), 7.21 (1H, brs), 7.33-7.38 (2H, m),7.50-7.55 (2H, m), 7.69 (1H, d, J=2.4 Hz), 8.07 (1H, d, J=5.6 Hz), 8.22(1H, m), 8.91 (1H, brs), 9.16 (1H, brs).

ESI-MS (m/z): 583 [M+Na]⁺.

Example 49N-Benzyl-N′-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were added benzylamine(0.018 ml), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 32 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (27.1 mg, 57%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.85 (8H, m), 2.00-2.15 (2H, m),2.29 (3H, s), 2.80-3.00 (5H, m), 4.18 (1H, m), 4.49 (2H, d, J=5.6 Hz),6.22 (1H, m), 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.85-6.95 (2H, m), 7.17 (1H,brs), 7.20-7.40 (5H, m), 7.69 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz),8.27 (1H, m), 10.72 (1H, brs).

ESI-MS (m/z): 575 [M+H]⁺.

Example 50N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(1-methylpiperidin-4-yl)cyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were added4-amino-1-methylpiperidine (18.8 mg), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 8 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (20.0 mg, 42%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.20 (16H, m), 2.29 (6H, s),2.70-3.00 (7H, m), 3.83 (1H, m), 4.17 (1H, m), 5.85 (1H, m), 6.52 (1H,dd, J=2.4, 5.6 Hz), 6.85-6.95 (2H, m), 7.20 (1H, brs), 7.69 (1H, d,J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.27 (1H, m), 10.68 (1H, brs).

ESI-MS (m/z): 582 [M+H]⁺.

Example 51N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-pyridin-3-ylcyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were added3-aminopyridine (15.5 mg), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 30 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (14.7 mg, 32%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.85 (8H, m), 2.00-2.15 (2H, m),2.30 (3H, s), 2.85-3.00 (5H, m), 4.17 (1H, m), 6.56 (1H, dd, J=2.4, 5.6Hz), 6.90-6.95 (2H, m), 7.10-7.30 (2H, m), 7.69 (1H, d, J=2.4 Hz), 8.08(1H, d, J=5.6 Hz), 8.13 (1H, m), 8.18 (1H, m), 8.30 (1H, brs), 8.38 (1H,dd, J=1.6, 4.8 Hz), 8.66 (1H, d, J=2.4 Hz), 9.87 (1H, brs).

ESI-MS (neg.) (m/z): 560 [M−H]⁻.

Example 52N-Cyclopentyl-N′-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were addedcyclopentylamine (0.0163 ml), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 25 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (23.2 mg, 51%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.25-1.90 (15H, m), 2.00-2.20 (4H, m),2.30 (3H, s), 2.85-3.00 (5H, m), 4.18 (1H, m), 5.82 (1H, m), 6.52 (1H,dd, J=2.4, 5.6 Hz), 6.85-6.92 (2H, m), 7.16 (1H, brs), 7.69 (1H, d,J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.27 (1H, m), 10.74 (1H, brs).

ESI-MS (m/z): 553 [M+H]⁺.

Example 53N-(2,2-Dimethylpropyl)-N′-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of1-(2-fluoro-4-{2-[3-methyl-3-(1-methylpiperidin-4-yl)ureido]pyridin-4-yloxy}phenyl)carbamoylcyclopropanecarboxylicacid (40 mg) in N,N-dimethylformamide (1.0 ml) were added neopentylamine(0.0194 ml), triethylamine (0.023 ml) andbenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(72.9 mg) at room temperature, followed by stirring for 22 hr.Liquid-liquid separation was carried out after addition of ethyl acetateand water to the reaction mixture. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate and brine, anddried over anhydrous sodium sulfate. The solvent was removed, and theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=97:3).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethylether:heptane=1:3 to the resultant residue. The solvent was removedunder reduced pressure. The solid residue was dried under reducedpressure to provide the titled compound as white powder (23.2 mg, 51%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 0.93 (9H, s), 1.50-1.90 (8H, m),2.00-2.20 (2H, m), 2.30 (3H, s), 2.85-3.00 (5H, m), 3.13 (2H, d, J=6.0Hz), 4.18 (1H, m), 6.07 (1H, m), 6.52 (1H, dd, J=2.4, 5.6 Hz), 6.85-6.95(2H, m), 7.17 (1H, brs), 7.69 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz),8.28 (1H, m), 10.60 (1H, brs).

ESI-MS (m/z): 577 [M+Na]⁺.

Example 54N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide

To a solution of[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) was added1-methyl-4-(piperidin-4-yl)piperazine (114 mg) at room temperature,followed by stirring for 5 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether to the resultant residue. The solid wascollected by filtration. The solid was dried under aeration to providethe titled compound as white powder (28.3 mg, 30%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.00 (9H, m), 2.29 (3H, s),2.35-2.70 (8H, m), 2.89 (2H, m), 4.05-4.15 (2H, m), 6.53 (1H, dd, J=2.4,5.6 Hz), 6.90-6.95 (2H, m), 7.15 (1H, m), 7.24 (1H, brs), 7.33-7.40 (2H,m), 7.50-7.55 (2H, m), 7.63 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz),8.22 (1H, m), 8.94 (1H, brs), 9.09 (1H, brs).

ESI-MS (m/z): 638 [M+Na]⁺.

Example 55N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-ylpiperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-phenylcyclopropane-1,1-dicarboxamide

To a solution of[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (100 mg) in N,N-dimethylformamide (2.0 ml) were added4-(3-dimethylaminoazetidin-1-yl)piperidine trihydrochloride (181 mg) andtriethylamine (0.259 ml) at room temperature, followed by stirring for 5days. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous solution ofammonium chloride and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=95:5).Fractions containing the target compound were concentrated under reducedpressure. A solid was precipitated by addition of diethyl ether to theresultant residue. The solid was collected by filtration. The solid wasdried under aeration to provide the titled compound as white powder(24.0 mg, 25%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.20-1.80 (8H, m), 2.12 (6H, s), 2.27(1H, m), 2.74-2.90 (3H, m), 3.05 (2H, m), 3.44-3.54 (2H, m), 3.80-3.94(2H, m), 6.53 (1H, dd, J=2.4, 5.6 Hz), 6.86-6.96 (2H, m), 7.14 (1H, m),7.22 (1H, brs), 7.32-7.40 (2H, m), 7.50-7.55 (2H, m), 7.62 (1H, d, J=2.4Hz), 8.05 (1H, d, J=5.6 Hz), 8.21 (1H, m), 8.99 (1H, brs), 9.03 (1H,brs).

ESI-MS (m/z): 616 [M+H]⁺.

Example 56N-(2,4-Difluorophenyl)-N′-(2-fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(4-{[1-(2,4-difluorophenylcarbamoyl)cyclopropanecarbonyl]amino}-3-fluorophenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (116 mg) in N,N-dimethylformamide (2.0 ml) was added1-methyl-4-(methylamino)piperidine (0.150 ml) at room temperature,followed by stirring overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=98:2). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:1 to the resultant residue. Thesolid was collected by filtration. The solid was dried under aeration toprovide the titled compound as white powder (14.0 mg, 14%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.85 (8H, m), 2.00-2.15 (2H, m),2.30 (3H, s), 2.85-3.00 (5H, m), 4.17 (1H, m), 6.54 (1H, dd, J=2.4, 5.6Hz), 6.80-7.30 (5H, m), 7.69 (1H, d, J=2.4 Hz), 8.07 (1H, d, J=5.6 Hz),8.18 (1H, m), 8.24 (1H, m), 9.02 (1H, brs), 9.18 (1H, brs).

ESI-MS (neg.) (m/z): 595 [M−H]⁻.

Example 57N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(2-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(3-fluoro-4-{[1-(2-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (90.6 mg) in N,N-dimethylformamide (2.0 ml) was added1-methyl-4-(methylamino)piperidine (0.120 ml) at room temperature,followed by stirring overnight. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with asaturated aqueous solution of ammonium chloride and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=98:2). Fractions containing the target compoundwere concentrated under reduced pressure. A solid was precipitated byaddition of diethyl ether:heptane=1:1 to the resultant residue. Thesolid was collected by filtration. The solid was dried under aeration toprovide the titled compound as white powder (30.2 mg, 38%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.85 (8H, m), 2.00-2.15 (2H, m),2.29 (3H, s), 2.85-3.00 (5H, m), 4.17 (1H, m), 6.54 (1H, dd, J=2.4, 5.6Hz), 6.80-7.30 (6H, m), 7.69 (1H, d, J=2.4 Hz), 8.07 (1H, d, J=5.6 Hz),8.20-8.30 (2H, m), 8.97 (1H, brs), 9.35 (1H, brs).

ESI-MS (neg.) (m/z): 577 [M−H]⁻.

Example 58N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) was added(3S)-(−)-3-dimethylaminopyrrolidine (44 mg), followed by stirring atroom temperature for 3.5 hr. The reaction mixture was partitionedbetween ethyl acetate and 1N sodium hydroxide. The organic layer waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas removed, and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, ethyl acetate:methanol=98:2). Fractionscontaining the target compound were concentrated. A solid wasprecipitated by addition of diethyl ether:hexane=1:2 to the residue. Thesolvent was removed, and the residue was dried under reduced pressure toprovide the titled compound as white powder (36.1 mg, 85%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 1.87 (1H, m), 2.17(1H, m), 2.27 (6H, s), 2.75 (1H, m), 3.22 (1H, m), 3.41 (1H, m), 3.66(1H, m), 3.73 (1H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.88-6.96 (2H, m),7.03 (1H, brs), 7.14 (1H, m), 7.32-7.40 (2H, m), 7.50-7.56 (2H, m), 7.70(1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.23 (1H, m), 8.98 (1H, brs),9.04 (1H, brs).

ESI-MS (m/z): 569 [M+Na]⁺.

Example 59N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide

To a solution of phenylN-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) in N,N-dimethylformamide (1.0 ml) was added3R)-(+)-3-dimethylaminopyrrolidine (44 mg), followed by stirring at roomtemperature for 3.5 hr. The reaction mixture was partitioned betweenethyl acetate and 1N sodium hydroxide. The organic layer was washed withbrine, and dried over anhydrous sodium sulfate. The solvent was removed,and the residue was purified by silica gel column chromatography (FujiSilysia NH, ethyl acetate:methanol=98:2). Fractions containing thetarget compound were concentrated. A solid was precipitated by additionof diethyl ether:hexane=1:2 to the residue. The solvent was removed, andthe residue was dried under reduced pressure to provide the titledcompound as white powder (33.2 mg, 79%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 1.87 (1H, m), 2.17(1H, m), 2.27 (6H, s), 2.75 (1H, m), 3.22 (1H, m), 3.41 (1H, m), 3.66(1H, m), 3.73 (1H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.88-6.96 (2H, m),7.03 (1H, brs), 7.14 (1H, m), 7.32-7.40 (2H, m), 7.50-7.56 (2H, m), 7.70(1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.23 (1H, m), 8.98 (11H,brs), 9.04 (11H, brs).

ESI-MS (m/z): 569 [M+Na]⁺.

Example 60N-(4-{[2-({[(1-Ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1′-dicarboxamide

To phenylN-[4-(3-fluoro-4-{[1-(phenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-phenoxycarbonylcarbamate(50.0 mg) was added a solution ofN-(1-ethylpiperidin-4-yl)-N-methylamine (66 mg) in N,N-dimethylformamide(1.0 ml), followed by stirring at room temperature for 9 hr. Thereaction mixture was partitioned between ethyl acetate and 1N sodiumhydroxide. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. The solvent was removed, and the residue waspurified by silica gel column chromatography (Fuji Silysia NH, ethylacetate, then ethyl acetate:methanol=98:2). Fractions containing thetarget compound were concentrated. A solid was precipitated by additionof diethyl ether:hexane=1:2 to the residue. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (25.8 mg, 58%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.08 (3H, t, J=7.2 Hz), 1.60-1.85 (8H,m), 2.03 (2H, m), 2.41 (2H, q, J=7.2 Hz), 2.89 (3H, s), 3.02 (2H, m),4.17 (1H, m), 6.54 (1H, dd, J=2.4, 5.6 Hz), 6.86-6.94 (2H, m), 7.15 (1H,m), 7.17 (1H, brs), 7.30-7.38 (2H, m), 7.50-7.56 (2H, m), 7.70 (1H, d,J=2.4 Hz), 8.06 (1H, d, J=5.6 Hz), 8.22 (1H, m), 8.92 (1H, brs), 9.13(1H, brs).

ESI-MS (m/z): 575 [M+H]⁺.

Production Example 62 4-(4-Amino-2-fluorophenoxy)pyridine-2-carboxamide

4-Amino-2-fluorophenol (9.63 g) was dissolved in dimethyl sulfoxide (100ml) under a nitrogen atmosphere. Potassium tert-butoxide (9.07 g) wasadded at room temperature, followed by stirring for 15 min.4-Chloropyridine-2-carboxamide (7.9 g) was added thereto, followed bystirring at 80° C. under a nitrogen atmosphere for 1 hr. The reactionmixture was allowed to cool down to room temperature. To the reactionmixture was added a 1N aqueous solution of sodium hydroxide (100 ml),then water (100 ml), followed by stirring for 5 hr. The precipitatedsolid was collected by filtration with suction, and washed with water(50 ml, 4 times). The resultant solid was hot air-dried at 60° C. for 2days to provide the titled compound as pale brown powder (10.39 g, 83%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.51 (2H, m), 6.44 (1H, dd, J=2.4,8.8 Hz), 6.53 (1H, dd, J=2.4, 13.2 Hz), 7.03 (1H, m), 7.14 (1H, dd,J=2.8, 5.6 Hz), 7.34 (1H, d, J=2.4 Hz), 7.71 (1H, brs), 8.11 (1H, brs),8.49 (1H, d, J=5.6 Hz).

Production Example 634-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide

To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylicacid (5.58 g) in tetrahydrofuran (60 ml) was added dropwisetriethylamine (4.18 ml) while cooling in an ice water bath under anitrogen atmosphere, followed by stirring for 15 min. To the reactionmixture, was then added thionyl chloride (2.0 ml), followed by stirringat the same temperature for 60 min. To the reaction mixture was added asuspension of 4-(4-amino-2-fluorophenoxy)pyridine-2-carboxamide (4.945g) and triethylamine (4.18 ml) in tetrahydrofuran (50 ml) while coolingin an ice water bath under a nitrogen atmosphere, followed by stirringfor 2 hr. The reaction was allowed to warm up to room temperature,followed by stirring overnight. The reaction mixture was partitionedafter addition of ethyl acetate (100 ml) and a 1N aqueous solution ofsodium hydroxide (100 ml). The organic layer was washed with a 2Naqueous solution of sodium hydroxide (100 ml, 3 times), 1N hydrochloricacid (100 ml, twice) and brine (100 ml) in this order, and dried overanhydrous sodium sulfate. The organic layer was filtered and thefiltrate was concentrated under reduced pressure. To the resultantresidue (8.3 g) were added ethyl acetate (20 ml) and heptane (5 ml) toprecipitate a solid. After diluting with addition of ethyl acetate (20ml), the solid was collected by filtration with suction, washed withethyl acetate-heptane (16 ml-2 ml). Drying under aeration with suctionon a paper filter provided the titled compound as pale brown powder(3.73 g, 41%). The filtrate was concentrated under reduced pressure, andethyl acetate (20 ml) and heptane (4 ml) were again added to the residue(3.6 g) to precipitate a solid. The solid was collected by filtrationwith suction. Drying under aeration with suction on a paper filterprovided the titled compound as pale brown powder (216 mg, 2.4%). Thefiltrate was further concentrated under reduced pressure, and theresidue (3.06 g) was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as pale brown powder (885 mg, 9.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.90 (4H, m), 5.78 (1H, m),6.95-7.30 (5H, m), 7.40-7.50 (2H, m), 7.64 (1H, d, J=2.4 Hz), 7.74 (1H,dd, J=2.4, 12.0 Hz), 7.88 (1H, m), 8.33 (1H, brs), 8.44 (1H, d, J=5.6Hz), 9.87 (1H, brs).

ESI-MS (m/z): 475 [M+Na]⁺.

Production Example 64N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

4-(2-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide(4.81 g) was dissolved in N,N-dimethylformamide (50 ml) under a nitrogenatmosphere, and water (0.5 ml), [bis(trifluoroacetoxy)iodo]benzene (5.17g) and pyridine (2.57 ml) were added in this order at room temperature,followed by stirring overnight. Water (0.5 ml),[bis(trifluoroacetoxy)iodo]benzene (5.17 g) and pyridine (2.57 ml) wereadded in this order at room temperature, followed by further stirringfor 1 hr. The reaction mixture was partitioned between ethyl acetate(200 ml) and water (100 ml). The organic layer was separated, washedwith brine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure and the residue was purified bysilica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate). Fractions containing the target compound were concentratedunder reduced pressure and the residue was dried under reduced pressureto provide the titled compound as pale brown foam (2.878 g, 64%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 4.84 (2H, brs), 5.94(1H, d, J=2.4 Hz), 6.31 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (6H, m), 7.69(1H, dd, J=2.4, 12.4 Hz), 7.89 (1H, d, J=5.6 Hz), 8.20 (1H, brs), 9.92(1H, brs).

ESI-MS (m/z): 425 [M+H]⁺.

Production Example 65N-(4-Fluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide

To a solution of 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid(1.02 g) in N,N-dimethylformamide (5.0 ml) were added triethylamine(1.28 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (2.03 g), followed by stirring at room temperaturefor 5 min. To this was added 4-amino-3-fluorophenol hydrochloride (500mg), followed by stirring at room temperature for 3 days. The reactionmixture was partitioned between ethyl acetate and a 1N aqueous solutionof sodium hydroxide. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide. To the aqueous layer was added 5Nhydrochloric acid to make it acidic, this was extracted with ethylacetate. The organic layer was washed with brine and dried overanhydrous sodium sulfate. The solvent was removed and the residue waspurified by silica gel column chromatography (eluent; heptane:ethylacetate=2:3 to 1:2). Fractions containing the target compound wereconcentrated under reduced pressure to provide the titled compound as apale red solid (395 mg, 39%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.80 (4H, m), 4.99 (1H, brs),6.60-6.70 (2H, m), 6.90-7.10 (2H, m), 7.45-7.55 (2H, m), 7.98 (1H, m),8.23 (1H, brs), 9.58 (1H, brs).

ESI-MS (m/z): 355 [M+Na]⁺.

Production Example 66 4-(4-Amino-3-fluorophenoxy)pyridine-2-carboxamide

4-Amino-3-fluorophenol (5.7 g) was dissolved in dimethyl sulfoxide (57ml) under a nitrogen atmosphere, and potassium tert-butoxide (5.6 g) wasadded at room temperature, followed by stirring for 15 min. To thereaction mixture was added 4-chloropicolylamide (5.0 g), followed bystirring in an oil bath at an external temperature of 80° C. under anitrogen atmosphere for 50 min. The reaction mixture was allowed to cooldown to room temperature. To the reaction mixture was added a 1N aqueoussolution of sodium hydroxide (85.5 ml), followed by stirring. Theprecipitated solid was collected by filtration, and washed with water.The solid was dried under aeration, then hot air-dried at 100° C. toprovide the titled compound as pale brown powder (5.88 g, 74.3%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.18-5.30 (2H, m), 6.80 (1H, dd,J=2.4, 8.4 Hz), 6.81-6.90 (1H, m), 7.02 (1H, dd, J=2.4, 11.6 Hz),6.99-7.14 (1H, m), 7.32-7.39 (1H, m), 7.69 (1H, brs), 8.10 (1H, brs),8.48 (1H, m).

Production Example 674-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide

N-(4-Fluorophenyl)-N′-(2-fluoro-4-hydroxyphenyl)cyclopropane-1,1-dicarboxamide(665 mg) was dissolved in N-methylpyrrolidone (10 ml) under a nitrogenatmosphere, and potassium tert-butoxide (247 mg) was added at roomtemperature, followed by stirring for 1.5 hr. After 4-chloropicolylamide(313 mg) was added, the reaction mixture was stirred under a nitrogenatmosphere at 110° C. overnight, then at 120° C. for 8 hr. The reactionmixture was allowed to cool down to room temperature. The reactionmixture was partitioned between ethyl acetate and water. The organiclayer was washed with a saturated aqueous solution of sodiumhydrogencarbonate (twice) and brine, and dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=1:2, 1:3, then 1:4). Fractions containing thetarget compound were concentrated under reduced pressure. After ethylacetate (3 ml)-heptane (6 ml) was added, crystals were allowed toprecipitate under sonication. The solvent was removed and the crystalswere dried under reduced pressure to provide the titled compound as palebrown crystals (261 mg, 29%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.80 (4H, m), 5.54 (1H, brs),6.90-7.30 (7H, m), 7.71 (1H, m), 7.86 (1H, brs), 8.28 (1H, m), 8.45 (1H,d, J=5.6 Hz), 8.94 (1H, brs), 9.14 (1H, brs).

ESI-MS (m/z): 475 [M+Na]⁺.

Alternative Method A for Synthesis of4-(3-Fluoro-4-{1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide

To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylicacid (1.45 g) in tetrahydrofuran (14.5 ml) was added dropwisetriethylamine (1.13 ml) under a nitrogen atmosphere while cooling in anice water bath, followed by stirring for 15 min. To the reaction mixturewas added thionyl chloride (0.473 ml), followed by stirring at the sametemperature for 1.5 hr. To the reaction mixture were added a solution of4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (1.0 g) intetrahydrofuran (10.5 ml) and triethylamine (1.13 ml) in this order atthe same temperature under a nitrogen atmosphere, followed by stirring.The reaction mixture was allowed to warm up to room temperature andstirred overnight. The reaction mixture was partitioned after additionof ethyl acetate (50 ml) and a 2N aqueous solution of sodium hydroxide(10 ml). The organic layer was washed with a 2N aqueous solution ofsodium hydroxide (10 ml, twice), 1N hydrochloric acid (10 ml, threetimes) and a saturated aqueous solution of sodium hydrogencarbonate (30ml), and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure, and the residue was filtered(eluent; ethyl acetate) through silica gel column (Fuji Silysia NH). Thefiltrate was concentrated under reduced pressure, and to the resultantresidue (1.28 g) were added ethyl acetate (4 ml) and heptane (4 ml) tosuspend. The solid was collected by filtration and dried under aerationto provide the titled compound as a pale pink solid (991.1 mg, 54.1%).The residue obtained by concentrating the filtrate under reducedpressure was purified by silica gel column chromatography (Fuji SilysiaNH, eluent; ethyl acetate:heptane=3:1). Fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as a white solid (24.3 mg, 1.33%).

Alternative Method B for Synthesis of4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide

To a solution of 1,1-cyclopropanedicarboxylic acid (3.12 g) intetrahydrofuran (90 ml) was added dropwise triethylamine (2.43 g) whilecooling in an ice water bath under a nitrogen atmosphere, followed bystirring for 1.5 hr. To the reaction mixture, was then added thionylchloride (1.75 ml), followed by stirring at the same temperature for 30min. To the reaction mixture were added4-(4-amino-3-fluorophenoxy)pyridine-2-carboxamide (2.97 g) andtriethylamine (2.43 g) in this order while cooling in an ice water bathunder a nitrogen atmosphere, followed by stirring for 70 min. Thereaction mixture was partitioned after addition of tert-butyl methylether (30 ml) and a 1N aqueous solution of sodium hydroxide (90 ml). Theaqueous layer was partitioned with tert-butyl methyl ether (30 ml)again, and the separated aqueous layer was treated with 1N hydrochloricacid to precipitate a solid. The solid was collected by suctionfiltration and washed with water (10 ml, four times). Drying underreduced pressure at 50° C. provided1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylicacid as a pale purple solid (1.90 g, 44%). After the filtrate was stoodovernight, further precipitated solid was collected by suctionfiltration and washed with water (10 ml, twice). Drying under reducedpressure provided additional1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylicacid as a pale purple solid (758 mg, 18%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.50-1.60 (4H, m), 7.07 (1H, dd,J=2.4, 8.8 Hz), 7.19 (1H, dd, J=2.4, 5.6 Hz), 7.35 (1H, m), 7.42 (1H, d,J=2.4 Hz), 7.72 (1H, m), 8.12 (1H, m), 8.24 (1H, m), 8.53 (1H, d, J=5.6Hz), 10.14 (1H, brs).

ESI-MS (neg.)(m/z): 358 [M−H]⁻.

To a suspension of1-[4-(2-carbamoylpyridin-4-yl)oxy-2-fluorophenylaminocarbonyl]cyclopropanecarboxylicacid (743 mg) and 4-fluoroaniline (459 mg) in tetrahydrofuran (30 ml)was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholiniumchloride hydrate (1.22 g), followed by stirring at room temperature for7.5 hr. The reaction mixture was partitioned between ethyl acetate andan aqueous solution of sodium hydrogencarbonate. The organic layer waswashed with water and dried over anhydrous magnesium sulfate. Thesolvent was concentrated under reduced pressure, and the resultantresidue was suspended by addition of tert-butyl methyl ether—ethylacetate (1:1, 20 ml). The solid was collected by filtration and driedunder aeration to provide the titled compound as a white solid (815 mg,87%).

Production Example 68N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide(101 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under anitrogen atmosphere, and water (0.01 ml),[bis(trifluoroacetoxy)iodo]benzene (109 mg) and pyridine (0.0541 ml)were added at room temperature in this order, followed by stirringovernight. Water (0.01 ml), [bis(trifluoroacetoxy)iodo]benzene (109 mg)and pyridine (0.0541 ml) were added at room temperature in this order,followed by further stirring for 24 hr. The reaction mixture waspartitioned between ethyl acetate and a 1N aqueous solution of sodiumhydroxide. The organic layer was separated, washed with brine, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure, and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate). Fractionscontaining the target compound were concentrated under reduced pressure,and the residue was dried under reduced pressure to provide the titledcompound as white foam (62.2 mg, 66%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.90 (4H, m), 4.90 (2H, brs), 5.98(1H, d, J=2.4 Hz), 6.33 (1H, dd, J=2.4, 5.6 Hz), 6.85-7.55 (6H, m), 7.90(1H, d, J=5.6 Hz), 8.20 (1H, m), 8.84 (1H, brs), 9.26 (1H, brs).

ESI-MS (m/z): 447 [M+Na]⁺.

Production Example 69N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidemonohydrochloride

4-(3-Fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridine-2-carboxamide(1.0 g) was dissolved in N,N-dimethylformamide (10 ml) under a nitrogenatmosphere, and water (0.199 ml), [bis(trifluoroacetoxy)iodo]benzene(1.96 g) and pyridine (1.07 ml) were added at room temperature in thisorder, followed by stirring for 33 hr. The reaction mixture waspartitioned after addition of ethyl acetate (30 ml) and a 1N aqueoussolution of sodium hydroxide (10 ml). The organic layer was washed witha 1N aqueous solution of sodium hydroxide (10 ml, twice) and brine (30ml) in this order, and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure. The resultant residue was dissolvedin ethyl acetate (10 ml), 5N hydrochloric acid (0.486 ml, 1.1equivalents) was added under sonication. The precipitated solid wascollected by filtration, washed with ethyl acetate, and dried underaeration for 1 hr. The solid was hot air-dried at 80° C. overnight toprovide the titled compound as pale brown powder (559.3 mg, 54.9%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.45-1.80 (4H, m), 6.14 (1H, d, J=2.4Hz), 6.65 (1H, dd, J=2.4, 6.8 Hz), 7.10-7.23 (3H, m), 7.42 (1H, dd,J=2.4, 11.6 Hz), 7.55-7.64 (21H, m), 7.77 (1H, m), 7.96 (1H, d, J=6.8Hz), 7.99-8.10 (1H, m), 9.88 (1H, brs), 10.79 (1H, brs).

Production Example 70 Morpholine-4-carboxylic acid[4-(4-nitrophenoxy)pyridin-2-yl]amide

4-(4-Nitrophenoxy)pyridin-2-ylamine (100 mg) was dissolved intetrahydrofuran (5 ml) under a nitrogen atmosphere, and triethylamine(0.181 ml) and phenyl chloroformate (0.163 ml) were added while stirringand cooling in an ice water bath. The reaction mixture was allowed towarm up to room temperature, followed by stirring for 30 min. Thereaction mixture was partitioned between ethyl acetate (50 ml) and asaturated aqueous solution of sodium hydrogencarbonate (30 ml). Theseparated organic layer was washed with water (30 ml) and brine (30 ml)in this order, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure. To the residue was addedN,N-dimethylformamide (5 ml), then morpholine (0.189 ml) was added,followed by stirring for 3 hr. The reaction mixture was concentratedunder reduced pressure, and the resultant residue was partitioned afteraddition of ethyl acetate (50 ml) and a saturated aqueous solution ofammonium chloride (30 ml). The separated organic layer was washed with asaturated aqueous solution of ammonium chloride (30 ml), water (30 ml)and brine (30 ml), and dried over anhydrous sodium sulfate. The solventwas removed under reduced pressure, and the residue was purified bysilica gel column chromatography (eluent; heptane:ethyl acetate=1:3,then ethyl acetate). Fractions containing the target compound wereconcentrated under reduced pressure to provide roughly-purified titledcompound as a pale yellow solid (128.8 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.52 (4H, m), 3.74 (4H, m), 6.68 (1H,dd, J=2.0, 5.6 Hz), 7.17-7.26 (2H, m), 7.67 (1H, m), 7.79 (1H, brs),8.15 (1H, d, J=5.6 Hz), 8.20-8.40 (2H, m).

Production Example 71 Morpholine-4-carboxylic acid[4-(4-aminophenoxy)pyridin-2-yl]amide

Morpholine-4-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (128mg) was dissolved in tetrahydrofuran (3 ml), and 20% palladium hydroxideon carbon (26.3 mg) was added at room temperature under a nitrogenatmosphere, followed by stirring under a hydrogen atmosphere for 7 hr.The atmosphere in the reaction vessel was replaced with nitrogen, andthe catalyst was removed by filtration and washed with tetrahydrofuran.The solvent was removed under reduced pressure to provide the titledcompound as a pale yellow solid (121 mg).

ESI-MS (m/z): 337 [M+Na]⁺.

Production Example 72 Pyrrolidine-1-carboxylic acid[4-(4-nitrophenoxy)pyridin-2-yl]amide

4-(4-Nitrophenoxy)pyridin-2-ylamine (100 mg) was dissolved intetrahydrofuran (5 ml) under a nitrogen atmosphere, triethylamine (0.181ml) and phenyl chloroformate (0.163 ml) were added while stirring andcooling in an ice water bath. The reaction mixture was allowed to warmup to room temperature and stirred for 30 min. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (30 ml). The separated organiclayer was washed with water (30 ml) and brine (30 ml) in this order, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. To the residue was added N,N-dimethylformamide (5 ml),and pyrrolidine (0.181 ml) was added, followed by stirring for 2 hr. Thereaction mixture was concentrated under reduced pressure, and theresultant residue was partitioned after addition of ethyl acetate (50ml) and a saturated aqueous solution of ammonium chloride (30 ml). Theseparated organic layer was washed with a saturated aqueous solution ofammonium chloride (30 ml), water (30 ml) and brine (30 ml), and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=1:3, then ethyl acetate).Fractions containing the target compound were concentrated under reducedpressure to provide the roughly-purified titled compound as a paleyellow solid (116.8 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.98 (4H, m), 3.48 (4H, m), 6.67 (1H,dd, J=2.4, 6.0 Hz), 7.18-7.34 (2H, m), 7.46 (1H, m), 7.88 (1H, dd, J=2.4Hz), 8.14 (1H, d, J=6.0 Hz), 8.25-8.35 (2H, m).

Production Example 73 Pyrrolidine-1-carboxylic acid[4-(4-aminophenoxy)pyridin-2-yl]amide

Pyrrolidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide(116.8 mg) was dissolved in tetrahydrofuran (3 ml), 20% palladiumhydroxide on carbon (25.0 mg) was added under a nitrogen atmosphere atroom temperature while stirring, followed by stirring under a hydrogenatmosphere for 7 hr. The atmosphere in the reaction vessel was replacedwith nitrogen, and the catalyst was removed by filtration and washedwith tetrahydrofuran. The solvent was removed under reduced pressure toprovide the titled compound as a pale yellow solid (112 mg).

ESI-MS (m/z): 321 [M+Na]⁺.

Production Example 74 Azetidine-1-carboxylic acid[4-(4-nitrophenoxy)pyridin-2-yl]amide

4-(4-Nitrophenoxy)pyridin-2-ylamine (100 mg) was dissolved intetrahydrofuran (5 ml) under a nitrogen atmosphere, triethylamine (0.181ml) and phenyl chloroformate (0.163 ml) were added while stirring andcooling in an ice water bath. The reaction mixture was allowed to warmup to room temperature and stirred for 30 min. The reaction mixture waspartitioned between ethyl acetate (50 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (30 ml). The separated organiclayer was washed with water (30 ml) and brine (30 ml) in this order, anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. To the residue was added N,N-dimethylformamide (5 ml),and azetidine monohydrochloride (203 mg) and triethylamine (0.483 ml)were added, followed by stirring overnight. The reaction mixture wasconcentrated under reduced pressure, the resultant residue waspartitioned after addition of ethyl acetate (50 ml) and a saturatedaqueous solution of ammonium chloride (30 ml). The separated organiclayer was washed with a saturated aqueous solution of ammonium chloride(30 ml), water (30 ml) and brine (30 ml), and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=1:3, then ethyl acetate). Fractions containing thetarget compound were concentrated under reduced pressure to provide theroughly-purified titled compound as a pale yellow solid (118.7 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.33 (2H, m), 4.11 (4H, m), 6.66 (1H,dd, J=2.4, 6.0 Hz), 7.15-7.25 (3H, m), 7.83 (1H, d, J=2.4 Hz), 8.13 (1H,d, J=6.0 Hz), 8.25-8.34 (2H, m).

Production Example 75 Azetidine-1-carboxylic acid[4-(4-aminophenoxy)pyridin-2-yl]amide

Azetidine-1-carboxylic acid [4-(4-nitrophenoxy)pyridin-2-yl]amide (118.7mg) was dissolved in tetrahydrofuran (6 ml), and 20% palladium hydroxideon carbon (26.6 mg) was added under a nitrogen atmosphere at roomtemperature while stirring, followed by stirring under a hydrogenatmosphere for 7 hr. The atmosphere in the reaction vessel was replacedwith nitrogen, and the catalyst was removed by filtration and washedwith tetrahydrofuran. The solvent was removed under reduced pressure toprovide the titled compound as a pale yellow solid (110 mg).

ESI-MS (m/z): 307 [M+Na]⁺.

Production Example 76 Benzyl4-(1-tert-butoxycarbonylpiperidin-4-yl)piperazine-1-carboxylate

Benzyl 1-piperazinecarboxylate (5.00 g) and tert-butyl4-oxopiperidine-1-carboxylate (4.52 g) were dissolved in methanol (100ml), and acetic acid (2.34 ml) and 10% palladium on carbon (1.55 g) wereadded thereto, followed by stirring under a hydrogen atmosphere for 4days. The catalyst was removed by filtration, and the filtrate wasconcentrated. To the residue were added acetone (50 ml) and water (50ml) to dissolve, and sodium hydrogencarbonate (6.67 g) was added andstirred while cooling in an ice bath. Benzyl chloroformate (3.89 ml) wasadded thereto, followed by stirring in an ice bath for 3.5 hr. Part ofthe reaction mixture was concentrated, and ethylacetate:tetrahydrofuran=1:1 (200 ml) and water (100 ml) were addedthereto, followed by stirring at room temperature for 10 min. Theorganic layer was separated. The organic layer was washed with brine,and dried over anhydrous sodium sulfate. This was concentrated, and theresidue was purified by silica gel column chromatography (eluent; ethylacetate, then ethyl acetate:methanol=50:1). Fractions containing thetarget compound were concentrated to provide the titled compound as apale yellow oil (2.71 g, 29.6%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40 (2H, m), 1.45 (9H, s), 1.77 (2H,m), 2.40 (1H, m), 2.52 (4H, m), 2.69 (2H, m), 3.51 (4H, m), 4.13 (2H,m), 5.13 (2H, s), 7.30-7.39 (5H, m).

ESI-MS (m/z): 426 [M+Na]⁺.

Production Example 77 Benzyl 4-(piperidin-4-yl)piperazine-1-carboxylate

To benzyl 4-(1-t-butoxycarbonylpiperidin-4-yl)piperazine 1-carboxylate(2.31 g) was added trifluoroacetic acid (10 ml) while cooling in an icebath, followed by stirring at room temperature for 3 hr. The reactionmixture was poured into ice water, and a 5N aqueous solution of sodiumhydroxide (26 ml) was added thereto. This was extracted with ethylacetate:tetrahydrofuran=1:1. The organic layer was washed with brine,and dried over anhydrous sodium sulfate. The solvent was removed toprovide the crude product of the titled compound as a pale yellow oil(1.93 g).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.57-1.66 (2H, m), 1.87 (2H, m),2.00-3.62 (14H, m), 5.14 (2H, m), 7.27-7.40 (5H, m).

ESI-MS (m/z): 304 [M+H]⁺.

Production Example 78 1-Benzhydrylazetidin-3-one

To a mixture of 1-benzhydrylazetidin-3-ol hydrochloride (5.52 g) andtriethylamine (27.9 ml) was added dropwise a solution of pyridine sulfurtrioxide complex (19.7 g) in dimethyl sulfoxide (80 ml) at roomtemperature. The reaction mixture was stirred at 50° C. for 30 min. Thereaction was allowed to cool down to room temperature. This was pouredinto ice water. This was extracted with ethyl acetate, and the organiclayer was washed with brine. Activated carbon (5 g) was added to theorganic layer, followed by stirring at room temperature for 3 days.Activated carbon was removed by filtration and the filtrate wasconcentrated. The residue was dissolved in methanol (200 ml), andactivated carbon (10 g) was added thereto, followed by stirring at roomtemperature for 3 days. Activated carbon was removed by filtration, andthe filtrate was concentrated. The residue was purified by silica gelcolumn chromatography (eluent; heptane:ethyl acetate=4:1, then 2:1).Fractions containing the target compound were concentrated to providethe target compound as a pale yellow oil (3.21 g). Hexane was addedthereto to precipitate crystals, which were collected by filtration.Drying under aeration provided the titled compound (1.11 g, 23.4%). Tothe residue obtained by concentrating the filtrate was added hexane, andallowed to stand at room temperature. After crystals precipitated,supernatant was removed by a pipette. This was dried under reducedpressure to provide the titled compound as pale yellow crystals (940 mg,19.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.01 (4H, s), 4.60 (1H, s), 7.22 (2H,m), 7.30 (4H, m), 7.48 (4H, m).

Production Example 79 3-(Azetidin-1-yl)-1-benzhydrylazetidine

To a solution of 1-benzhydrylazetidin-3-one (750 mg) in dichloromethane(12 ml) was added azetidine hydrochloride (326 mg), followed by stirringat room temperature. Sodium triacetoxy borohydride (1.01 g) was addedthereto, followed by stirring at room temperature for 25 hr. To thereaction mixture were added sodium carbonate (until bubbling stopped),water (50 ml) and ethyl acetate (100 ml). The organic layer wasseparated. This was washed with brine, and dried over anhydrous sodiumsulfate. The organic layer after drying was concentrated under reducedpressure. The residue was purified by silica gel column chromatography(Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2, then ethylacetate) to provide the titled compound as a pale yellow solid (643 mg,73.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.06 (2H, m), 2.91 (2H, m), 3.16-3.24(7H, m), 4.35 (1H, s), 7.15 (2H, m), 7.25 (4H, m), 7.40 (4H, d, J=7.6Hz).

ESI-MS (m/z): 279 [M+H]⁺.

Production Example 80 3-(Azetidin-1-yl)azetidine dihydrochloride

To a solution of 3-(azetidin-1-yl)-1-benzhydrylazetidine (643 mg) inethyl acetate was added a 4N solution of hydrochloric acid in ethylacetate (1.16 ml), followed by concentration. The resultant residue wasdissolved in methanol (65 ml), and 20% palladium hydroxide (811 mg) wasadded thereto. This was stirred at room temperature under a pressurizedhydrogen atmosphere (0.3 to 0.4 MPa) for 4 hr. The catalyst was removedby filtration, and the filtrate was concentrated. Hexane was added tothe residue to suspend a solid. The residue after removing a supernatantby a pipette was concentrated under reduced pressure to provide a crudeproduct of the titled compound as a pale yellow oil (471.2 mg).

ESI-MS (m/z): 113 [M+H]⁺.

Production Example 81 1-Benzhydryl-3-(methanesulfonyloxy)azetidine

A suspension of 1-benzhydrylazetidin-3-ol (15.0 g) in pyridine (100 ml)was cooled to −20° C. under a nitrogen atmosphere, and methanesulfonylchloride (6.33 ml) was added dropwise thereto. The reaction mixture wasstirred under a nitrogen atmosphere at −20° C. for 1 hr, then in a waterbath for 2.5 days. The reaction mixture was partitioned after additionof water and ethyl acetate. The organic layer was washed with asaturated aqueous solution of sodium hydrogencarbonate, water and brine,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. To the residue were added ethanol (10 ml) andhexane (50 ml) to suspend precipitated crystals. The crystals werecollected by filtration and washed with hexane. This was dried underaeration at room temperature to provide the titled compound as paleyellow crystals (5.943 g, 44.8%). The filtrate was concentrated, and theresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=2:1, 1:1, then heptane:ethylacetate:methanol=50:50:1, 40:60:1, then ethyl acetate:methanol=100:1).Fractions containing the target compound were concentrated to providethe titled compound as pale yellow crystals (1.58 g, 11.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.99 (3H, s), 3.18-3.21 (2H, m),3.62-3.66 (2H, m), 4.40 (1H, s), 5.11 (1H, m), 7.18-7.22 (2H, m),7.26-7.31 (4H, m), 7.39 (4H, d, J=7.2 Hz).

Production Example 82 1-Benzhydryl-3-cyanoazetidine

To a solution of 1-benzhydryl-3-(methanesulfonyloxy)azetidine (7.52 g)in N,N-dimethylformamide (60 ml) were added water (7.2 ml) and sodiumcyanide (3.48 g), followed by stirring at 65° C. for 9 hr. To thereaction mixture were added water, sodium carbonate and ethyl acetate,and this was partitioned. The aqueous layer was extracted with ethylacetate. The organic layer was combined, washed with brine, and driedover anhydrous sodium sulfate. This was concentrated under reducedpressure, and the resultant crystals were suspended by addition ofdiethyl ether (10 ml). The crystals were collected by filtration andwashed with diethyl ether. This was dried under aeration to provide thetitled compound as pale yellow crystals (5.43 g, 92.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.20-3.31 (3H, m), 3.47 (2H, m), 4.36(1H, s), 7.19-7.23 (2H, m), 7.26-7.30 (4H, m), 7.39 (4H, m).

Production Example 83 1-Benzhydrylazetidine-3-carboxylic acid

To a solution of 1-benzhydryl-3-cyanoazetidine (5.43 g) inmethoxyethanol (54 ml) were added potassium hydroxide (6.48 g) and water(3.25 ml), followed by stirring at 100° C. for 4 hr. The reactionmixture was allowed to cool down to room temperature. The reactionmixture was poured into ice. After adjusting this to pH 5 with 1Nhydrochloric acid, sodium chloride was added thereto. This was extractedwith a mixed solvent of ethyl acetate and tetrahydrofuran. The organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The organic layer after drying was concentrated under reduced pressureto provide a crude product of the titled compound as pale yellowcrystals. The crystals were suspended by addition of diethyl ether (15ml). The crystals were collected by filtration and washed with diethylether. This was dried under aeration to provide the titled compound aspale yellow crystals (4.20 g, 71.7%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.00-3.90 (5H, m), 4.95 (1H, s),7.25-7.28 (2H, m), 7.33 (4H, m), 7.53 (4H, m).

Production Example 84 Methyl 1-benzhydrylazetidine-3-carboxylate

A solution of 1-benzhydrylazetidine-3-carboxylic acid (4.20 g) inN,N-dimethylformamide (45 ml) were added potassium carbonate (6.53 g)and iodomethane (0.976 ml), followed by stirring at room temperature for20.5 hr. The reaction mixture was poured into ice water, and extractedwith ethyl acetate. The organic layer was washed with brine, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=5:1, then 3:1). Fractions containing the target compound wereconcentrated to provide the titled compound as yellow crystals (3.57 g,80.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.26 (2H, m), 3.31 (1H, m), 3.44 (2H,m), 3.69 (3H, s), 4.38 (1H, s), 7.16-7.20 (2H, m), 7.25-7.28 (4H, m),7.39-7.41 (4H, m).

ESI-MS (m/z): 282 [M+H]⁺.

Production Example 85 Methyl azetidine-3-carboxylate hydrochloride

A solution of methyl 1-benzhydrylazetidine-3-carboxylate (3.57 g) inmethanol (360 ml) were added a 4N solution of hydrochloric acid in ethylacetate (12.7 ml) and 20% palladium hydroxide (3.57 g), followed bystirring at room temperature under a pressurized hydrogen atmosphere(0.4 MPa) for 11 hr. The catalyst was removed by filtration and washedwith methanol and water. The filtrate was concentrated to provide acrude product of the target compound as a pale yellow oil. The reactionwas assessed as quantitative and the product obtained was assessed as1.93 g, which were used for the subsequent reaction.

ESI-MS (m/z): 116 [M+H]⁺.

Production Example 86 Methyl1-tert-butoxycarbonylazetidine-3-carboxylate

A crude product of methyl azetidine-3-carboxylate hydrochloride(assessed as 1.93 g of a pure product) was dissolved in water (26 ml),and sodium hydrogencarbonate (3.2 g) and a solution of di-t-butyldicarbonate (2.91 g) in tetrahydrofuran (13 ml) were added whilestirring and cooling in an ice bath, followed by stirring at the sametemperature for 0.5 hr. The reaction mixture was stirred at roomtemperature for 19.5 hr. Tetrahydrofuran in the reaction mixture wasremoved, and extracted with ethyl acetate. The organic layer was washedwith brine (70 ml), and dried over anhydrous sodium sulfate. Theconcentrated organic layer and the aqueous layer were combined, andtetrahydrofuran (50 ml) was added. This was stirred while cooling in anice bath, and sodium hydrogencarbonate (3.2 g), and di-t-butyldicarbonate (2.91 g) were again added thereto. After stirring at thesame temperature for 0.5 hr, stirring was carried out at roomtemperature for 2.5 days. The reaction mixture was partitioned, and theaqueous layer was extracted with ethyl acetate. The organic layer wascombined and dried over anhydrous sodium sulfate. The solvent wasremoved, and the residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=2:1, 1:1, ethyl acetate,then ethyl acetate:methanol=10:1). Fractions containing the targetcompound were concentrated to provide the titled compound as a colorlessoil (370 mg, 13.5%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (9H, s), 3.35 (1H, m), 3.75 (3H,s), 4.10 (4H, d, J=7.6 Hz).

Production Example 87 tert-Butyl3-(hydroxymethyl)azetidine-1-carboxylate

Lithium aluminum hydride (128 mg) was placed in a round-bottomed flaskand suspended in tetrahydrofuran (30 ml). This was cooled in an icebath, and a solution of methyl1-tert-butoxycarbonylazetidine-3-carboxylate (970 mg) in tetrahydrofuran(10 ml) was gradually added thereto, followed by stirring under anitrogen atmosphere at the same temperature for 1 hr. To the reactionmixture were added water (0.13 ml) and a 5N aqueous solution of sodiumhydroxide (0.13 ml) and water (0.39 ml) while cooling in an ice bath,followed by stirring at the same temperature for 1 hr. Insoluble matterin the reaction mixture was removed by filtration. The filtrate wasconcentrated to provide the titled compound as a colorless oil (805 mg,95.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (9H, s), 2.71 (1H, m), 3.69 (2H,dd, J=5.2, 8.4 Hz), 3.79 (2H, d, J=6.8 Hz), 4.00 (2H, m).

Production Example 88 3-(Hydroxymethyl)azetidine trifluoroacetate

To tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (125 mg) wasadded trifluoroacetic acid (0.413 ml) while cooling in an ice bath,followed by stirring at the same temperature for 30 min. Then, thereaction mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was concentrated to provide a crude product of thetitled compound as a yellow oil (209.8 mg).

ESI-MS (m/z): 88 [M+H]⁺.

Production Example 89 tert-Butyl3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate

To a solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate(806 mg) in tetrahydrofuran (25 ml) was added triethylamine (1.80 ml).This was cooled in an ice bath under a nitrogen atmosphere, andmethanesulfonyl chloride (0.499 ml) was added dropwise, followed bystirring at the same temperature for 30 min. The reaction mixture waspartitioned after addition of ethyl acetate (100 ml) and water (70 ml).The aqueous layer was extracted with ethyl acetate. The combined organiclayer was washed with brine, and dried over anhydrous sodium sulfate.The solvent was removed, and the residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate). Fractions containing thetarget compound were concentrated to provide the titled compound as acolorless oil (1.05 g, 92.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (9H, s), 2.93 (1H, m), 3.05 (3H,s), 3.72 (2H, dd, J=5.0, 9.0 Hz), 4.06 (2H, m), 4.35 (2H, d, J=6.8 Hz).

ESI-MS (m/z): 288 [M+Na]⁺.

Production Example 90 tert-Butyl3-(dimethylaminomethyl)azetidine-1-carboxylate

To a solution of tert-butyl3-[(methanesulfonyloxy)methyl]azetidine-1-carboxylate (1.05 g) inmethanol (20 ml) was added a 2M solution of dimethylamine intetrahydrofuran (20 ml), followed by heating in a sealed tube at 70° C.for 40 hr. The reaction mixture was allowed to cool down to roomtemperature. The reaction mixture was concentrated, and partitionedbetween ethyl acetate and a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was washed with brine, and driedover anhydrous sodium sulfate. The solvent was removed to provide thetitled compound as a yellow oil (678 mg, 79.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.43 (9H, s), 2.22 (6H, s), 2.50 (2H,d, J=7.6 Hz), 2.69 (1H, m), 3.59 (2H, dd, J=5.2, 8.4 Hz), 4.16 (2H, m).

ESI-MS (m/z): 215 [M+H]⁺, 269 [M+Na+MeOH]⁺.

Production Example 91 3-(Dimethylaminomethyl)azetidineditrifluoroacetate

To tert-butyl 3-(dimethylaminomethyl)azetidine-1-carboxylate (678 mg)was added trifluoroacetic acid (1.95 ml) while cooling in an ice bath,followed by stirring at the same temperature for 30 min. Then, thereaction mixture was stirred at room temperature for 1.5 hr. Thereaction mixture was concentrated, then azeotropically distilled afteraddition of toluene to provide a crude product of the titled compound asa yellow oil (1.79 g).

ESI-MS (m/z): 115 [M+Na]⁺.

Production Example 92 tert-Butyl 3-methoxyazetidine-1-carboxylate

A suspension of sodium hydride (2.89 g) in tetrahydrofuran (50 ml) wasstirred while cooling in an ice bath. A solution of tert-butyl3-hydroxyazetidine-1-carboxylate (5.00 g) in tetrahydrofuran (50 ml) wasgradually added thereto, followed by stirring at the same temperaturefor 30 min. Then, the reaction mixture was stirred at room temperaturefor 30 min. The reaction mixture was again stirred while cooling in anice bath for 15 min. To the reaction mixture was added dropwiseiodomethane (3.09 ml), followed by stirring for 2 hr. Water wasgradually added to the reaction mixture. When bubbling stopped, theorganic layer was separated. The aqueous layer was extracted with ethylacetate. The organic layer was combined, washed with brine, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=3:1, 2:1, 1:1, then ethyl acetate). Fractions containing thetarget compound were concentrated to provide the titled compound as acolorless oil (1.80 g, 33.3%). Fractions containing the startingmaterial were concentrated for recovery (2.10 g, 42.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44 (9H, s), 3.28 (3H, s), 3.82 (2H,m), 4.06 (2H, m), 4.14 (1H, m).

Production Example 93 3-Methoxyazetidine trifluoroacetate

tert-Butyl 3-methoxyazetidine-1-carboxylate (125 mg) was dissolved indichloromethane (0.618 ml), and trifluoroacetic acid (0.618 ml) wasadded thereto, followed by stirring at room temperature for 3.5 hr. Thereaction mixture was concentrated to provide a crude product of thetarget compound as a yellow oil (232 mg).

ESI-MS (m/z): 88 [M+H]⁺.

Production Example 94 1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene

To a solution of 2,4,5-trifluoronitrobenzene (9.48 g) and benzyl alcohol(5.54 ml) in N,N-dimethylformamide (40 ml) was added potassium carbonate(11.1 g), followed by stirring at room temperature for 60 hr. To thereaction mixture was added water (120 ml) at 0° C., followed by stirringat 4° C. for 24 hr. The precipitated crystals were collected byfiltration and washed with water. These crystals were dried underreduced pressure to provide the titled compound as pale yellow crystals(11.5 g, 81%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.35 (2H, s), 7.40-7.50 (5H, m), 7.64(1H, dd, J=7.2, 13.2 Hz), 8.20 (1H, dd, J=7.2, 10.8 Hz).

Production Example 95 4-Amino-2,5-difluorophenol

To a solution of 1-(benzyloxy)-2,5-difluoro-4-nitrobenzene (9.21 g) inmethanol (300 ml) was added 10% palladium on carbon (921 mg), followedby stirring under a hydrogen atmosphere at room temperature for 24 hrand 20 min. The atmosphere in the reaction vessel was replaced withnitrogen to stop the reaction, and the catalyst was filtered throughCelite. The filtrate was removed under reduced pressure to provide thetitled compound as a brown solid (4.96 g, 99%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 4.67 (1H, s), 6.53-6.64 (1H, m), 9.03(1H, s).

Production Example 964-(4-Amino-2,5-difluorophenoxy)pyridine-2-carboxamide

4-Amino-2,5-difluorophenol (4.95 g) was dissolved in dimethyl sulfoxide(50 ml) under a nitrogen flow, and potassium tert-butoxide (4.05 g) wasadded at room temperature, followed by stirring for 25 min.4-Chloropyridine-2-carboxamide (2.70 g) was added thereto, followed bystirring at 80° C. for 2.5 hr. The reaction mixture was allowed to cooldown to room temperature, and a 1N aqueous solution of sodium hydroxide(74.25 ml) was added, followed by stirring for 10 hr. The precipitatedsolid was collected by filtration, and the resultant solid was washedwith water. This solid was dried under hot air at 100° C. for 24 hr toprovide the titled compound as purple powder (3.38 g, 74%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 5.57 (2H, d, J=6.0 Hz), 6.75-6.80(1H, m), 7.17-7.20 (1H, m), 7.26 (1H, dd, J=7.2, 10.8 Hz), 7.38 (1H, m),7.73 (1H, s), 8.14 (1H, s), 8.52 (1H, d, J=5.6 Hz).

ESI-MS (m/z): 288 [M+Na]⁺.

Production Example 97N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

1-(4-Fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.35 g) wasdissolved in tetrahydrofuran (25.0 ml) under a nitrogen atmosphere, andtriethylamine (1.06 ml) was added dropwise while cooling in an ice waterbath, followed by stirring for 15 min. Then thionyl chloride (0.439 ml)was added at the same temperature, followed by stirring for 1.5 hr. Tothe reaction mixture was added dropwise at the same temperature amixture of 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (1.0g), tetrahydrofuran (12 ml) and triethylamine (1.06 ml), followed bystirring at 0° C. for 24 hr and 45 min. The reaction mixture waspartitioned between ethyl acetate (70 ml) and a 2N aqueous solution ofsodium hydroxide (15 ml). The organic layer was washed with a 2N aqueoussolution of sodium hydroxide (15 ml) twice, 1N hydrochloric acid (15 ml)three times and a saturated aqueous solution of sodium hydrogencarbonate(10 ml) in this order, and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure. The resultant residue waspurified by silica gel column chromatography (Fuji Silysia NH, eluent;heptane:ethyl acetate=1:1, 1:2, then ethyl acetate), and fractionscontaining the target compound were concentrated under reduced pressure.The residue was dried under reduced pressure to provide the titledcompound as a white solid (372.8 mg, 21%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.28-1.33 (4H, m), 7.12-7.22 (2H, m),7.22-7.28 (1H, m), 7.41 (1H, d, J=2.4 Hz), 7.59-7.67 (3H, m), 7.75 (1H,m), 8.10-8.17 (2H, m), 8.56 (1H, d, J=5.6 Hz), 9.80 (1H, m), 11.02 (1H,m).

Alternative Method for Synthesis ofN-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-carboxamide

To a solution of 1,1-cyclopropanedicarboxylic acid (492 mg) intetrahydrofuran (15 ml) was added dropwise 4-methylmorpholine (0.416 ml)while cooling in an ice water bath under a nitrogen atmosphere, followedby stirring for 15 min. To the reaction mixture, was then added thionylchloride (0.276 ml), followed by stirring at the same temperature for 30min. To the reaction mixture were added4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (500 mg) and4-methylmorpholine (0.416 ml) in this order while cooling in an icewater bath under a nitrogen atmosphere. The reaction mixture was allowedto warm to room temperature and stirred overnight. The reaction mixturewas partitioned after addition of a 1N aqueous solution of sodiumhydroxide (15 ml) and tert-butyl methyl ether (30 ml). The separatedaqueous layer was treated with 1N hydrochloric acid (15 ml) toprecipitate a solid. The solid was collected by suction filtration andwashed with water (10 ml, three times). Hot air drying at 60° C.provided1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylicacid as a pale purple solid (674 mg, 95%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.53-1.65 (4H, m), 7.25 (1H, dd,J=2.4, 5.6 Hz), 7.44 (1H, d, J=2.4 Hz), 7.65-7.70 (1H, m), 7.75 (1H,brs), 8.15 (1H, brs), 8.26-8.31 (1H, m), 8.55 (1H, d, J=5.6 Hz), 11.48(1H, brs).

ESI-MS (neg.)(m/z): 376 [M−H]⁻.

To a suspension of1-[4-(2-carbamoylpyridin-4-yl)oxy-2,5-difluorophenylaminocarbonyl]cyclopropanecarboxylicacid (100 mg) and 4-fluoroaniline (0.051 ml) in tetrahydrofuran (4 ml)was added 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholiniumchloride hydrate (157 mg), followed by stirring at room temperature 23hr. The reaction mixture was partitioned between ethyl acetate and anaqueous solution of sodium hydrogencarbonate. The organic layer waswashed with water and brine, dried over anhydrous magnesium sulfate. Thesolvent was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; heptane:ethyl acetate=1:2, ethyl acetate, then ethylacetate:methanol=10:1), and fractions containing the target compoundwere concentrated under reduced pressure. The residue was dried underreduced pressure to provide the titled compound as a white solid (133.5mg, quant.).

ESI-MS (m/z): 493 [M+Na]⁺.

Production Example 98N-(4-{[2-(Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(372.8 mg) was dissolved in N,N-dimethylformamide (5.0 ml). Water(0.0713 ml), [bis(trifluoroacetoxy)iodo]benzene (679 mg) and pyridine(0.384 ml) were added thereto at room temperature in this order,followed by stirring for 3 hr. The reaction mixture was partitionedbetween ethyl acetate (30 ml) and a 1N aqueous solution of sodiumhydroxide (9 ml). The organic layer was separated, washed with brine,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure, and the residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent;heptane:ethylacetate=1:3, then ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure, and the residue wasdried under reduced pressure to provide the titled compound as whitepowder (301.0 mg, 86%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.54-1.68 (4H, m), 5.83 (1H, d, J=2.4Hz), 5.99 (2H, d, J=5.2 Hz), 6.17 (1H, dd, J=2.4, 5.6 Hz), 7.16-7.20(2H, m), 7.47-7.53 (1H, m), 7.57-7.62 (2H, m), 7.81 (1H, d, J=5.6 Hz),8.02-8.10 (1H, m), 9.77 (1H, m), 10.99 (1H, m).

ESI-MS (m/z): 443 [M+H]⁺.

Production Example 99 3-(Azetidin-1-ylcarbonyl)-1-benzhydrylazetidine

1-Benzhydrylazetidine-3-carboxylic acid (1.52 g) was dissolved inN,N-dimethylformamide (30 ml) at room temperature under a nitrogenatmosphere. Triethylamine (3.17 ml), BOP reagent (5.03 g), and azetidinehydrochloride (1.06 g) were added in this order, followed by stirringfor 24 hr. To the reaction mixture was added a 1N aqueous solution ofsodium hydroxide (50 ml), followed by stirring. The liquid-liquidseparation was carried out after addition of ethyl acetate (100 ml). Theseparated organic layer was washed with a 1N aqueous solution of sodiumhydroxide, water and brine in this order, and dried over anhydroussodium sulfate. To the residue (1.83 g) obtained by removing the solventwere added ethyl acetate (2 ml) and tert-butyl methyl ether (10 ml) toprecipitate crystals. The crystals were collected by filtration anddried under aeration to provide the titled compound as pale yellowcrystals (1.14 g, 65%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.15-2.30 (2H, m), 3.20-3.50 (5H, m),3.90-4.10 (4H, m), 4.45 (1H, s), 7.15-7.45 (10H, m).

ESI-MS (m/z): 307 [M+H]⁺.

Production Example 100 3-(Azetidin-1-ylmethyl)-1-benzhydrylazetidine

Lithium aluminum hydride (300 mg) was suspended in tetrahydrofuran (10ml) under a nitrogen atmosphere at room temperature, and a solution of3-(azetidin-1-ylcarbonyl)-1-benzhydrylazetidine (1.14 g) intetrahydrofuran (30 ml) was added dropwise. After the dropwise addition,the reaction mixture was stirred at 60° C. for 2 hr. The reactionmixture was cooled in an ice water bath, and water (0.3 ml), a 5Naqueous solution of sodium hydroxide (0.3 ml) and water (0.9 ml) wereadded, followed by stirring overnight. Insoluble matter was removed byfiltration and washed with ethyl acetate (100 ml). The filtrate wasconcentrated under reduced pressure to provide the titled compound as apale brown oil (1.115 g, quantitative).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.07 (2H, m), 2.40-2.60 (3H, m), 2.74(2H, m), 3.11-3.15 (4H, m), 3.32 (2H, m), 4.29 (1H, s), 7.14-7.40 (10H,m).

ESI-MS (m/z): 293 [M+H]⁺.

Production Example 101 3-(Azetidin-1-ylmethyl)azetidine dihydrochloride

3-(Azetidin-1-ylmethyl)-1-benzhydrylazetidine (1.115 g) was dissolved inmethanol (25 ml). Then, 10% palladium on carbon (1.1 g) wad added undera nitrogen atmosphere, followed by stirring under a pressurized hydrogenatmosphere (0.4 MPa) for 12 hr. The atmosphere in the reaction vesselwas replaced with nitrogen, and the catalyst was removed by filtrationand washed with methanol. To the filtrate was added a 4N solution ofhydrochloric acid in ethyl acetate (4 ml), followed by concentrationunder reduced pressure. To the residue was added heptane (25 ml), andthe supernatant was removed. This operation was repeated once more. Theresultant residue was dried under reduced pressure for 2 days to providethe titled compound as a pale brown oil (680 mg, 90%).

ESI-MS (m/z): 127 [M+H]⁺.

Production Example 102 1-Benzhydryl-3-(hydroxymethyl)azetidine

1-Benzhydryl-3-azetidinecarboxylic acid (3.12 g) was suspended intetrahydrofuran (60 ml) and cooled under a nitrogen atmosphere in anice-ethanol bath. Triethylamine (1.96 ml) was added dropwise, and asolution of ethyl chlorocarbonate (1.34 ml) in tetrahydrofuran (5 ml)was added dropwise over 20 min. After the dropwise addition, stirringwas carried out at the same temperature for 30 min. The reaction mixturewas filtered and washed with tetrahydrofuran (30 ml). The filtrate wasadded dropwise over 15 min to an aqueous (15 ml) solution of sodiumborohydride (1.33 g) cooled in an ice water bath. Upon completion of thedropwise addition, the reaction mixture was stirred at room temperature.To the reaction mixture was gradually added 1N hydrochloric acid (35 ml)to decompose excess sodium borohydride, and a 1N aqueous solution ofsodium hydroxide (35 ml) was added. This was extracted with ethylacetate (100 ml). The organic layer was washed with brine, and driedover anhydrous sodium sulfate. The solvent was concentrated, and theresidue was dried under reduced pressure to provide the titled compoundas a pale brown solid (1.59 g, 54%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 2.57 (1H, m), 3.03 (2H, m), 3.24 (2H,m), 3.80 (2H, d, J=5.2 Hz), 4.33 (1H, s), 7.15-7.45 (10H, m).

ESI-MS (m/z):254[M+H]⁺.

Production Example 103 3-(Hydroxymethyl)azetidine

hydrochloride 1-Benzhydryl-3-(hydroxymethyl)azetidine (1.59 g) wasdissolved in methanol (30 ml), and palladium hydroxide on carbon (1.0 g)was added under a nitrogen atmosphere, followed by stirring under apressurized hydrogen atmosphere (0.4 MPa). The atmosphere in thereaction vessel was replaced with nitrogen, and the catalyst wasfiltered and washed with methanol. After addition of a 4N solution ofhydrochloric acid in ethyl acetate (2 ml), concentration under reducedpressure was carried out. To the residue was added heptane (15 ml), andthe supernatant was removed. This operation was repeated. The residuewas dried under reduced pressure overnight to provide a crude product ofthe titled compound as a pale yellow oil (832 mg).

ESI-MS (m/z): 88 [M+H]⁺.

Production Example 104 Benzyl (2,5-difluoro-4-hydroxyphenyl)carbamate

1-(Benzyloxy)-2,5-difluoro-4-nitrobenzene (5.3 g) was dissolved inmethanol (100 ml)-tetrahydrofuran (100 ml). 20% palladium hydroxide oncarbon (2.81 g) was added thereto, followed by stirring under a hydrogenatmosphere at room temperature for 8 hr. The catalyst was removed byfiltration and washed with methanol. The filtrate was concentrated underreduced pressure. The resultant residue (3.06 g) was dissolved inacetone (100 ml)-water (50 ml). Sodium carbonate (2.02 g) and benzylchloroformate (3.43 ml) were added thereto while stirring and cooling inan ice water bath, followed by stirring at room temperature for 1 hr.The reaction mixture was concentrated under reduced pressure. Theresidue was partitioned between ethyl acetate and brine. The organiclayer was separated and concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography(eluent; heptane:ethyl acetate=2:1). Fractions containing the targetcompound were concentrated under reduced pressure and the residue wasdried under reduced pressure to provide the titled compound as a brownsolid (4.90 g, 88%).

ESI-MS (neg.) (m/z): 278 [M−H]⁻.

Production Example 105 Benzyl[4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate

Benzyl (2,5-difluoro-4-hydroxyphenyl)carbamate (4.90 g) was dissolved inN,N-dimethylformamide (30 ml), then 4,6-dichloropyrimidine (2.61 g) andpotassium carbonate (3.63 g) were added thereto at room temperature,followed by stirring for 2 hr. Water (90 ml) was added to the reactionmixture to precipitate crystals. The crystals were collected byfiltration and washed with water (30 ml, 6 times). The crystals were hotair-dried at 60° C. for 2 days to provide the titled compound as palebrown crystals (6.108 g, 89%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.25 (2H, s), 6.95 (1H, brs), 7.01 (1H,m), 7.04 (1H, d, J=0.8 Hz), 7.30-7.50 (5H, m), 8.16 (1H, m), 8.56 (1H,d, J=0.8 Hz).

ESI-MS (neg.) (m/z): 390 [M−H]⁻.

Production Example 106 Benzyl[4-(4-aminopyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate

A mixture of benzyl[4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (3.92 g) and2M ammonia-isopropanol (50 ml) was heated at 120° C. for 2 days in asealed tube. The reaction mixture was allowed to cool to roomtemperature, then concentrated under reduced pressure. The resultantresidue was partitioned between ethyl acetate and a 10% aqueous solutionof potassium bisulfate. The organic layer was washed with brine, driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; heptane:ethylacetate=1:2). Fractions containing the target compound were concentratedunder reduced pressure and the residue was dried under reduced pressureto provide the titled compound as pale yellow crystals (561 mg, 15%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 4.94 (2H, br), 5.23 (2H, s), 5.97 (1H,d, J=0.8 Hz), 6.91 (1H, brs), 6.99 (1H, m), 7.30-7.50 (5H, m), 8.10 (1H,m), 8.24 (1H, d, J=0.8 Hz).

ESI-MS (m/z): 395 [M+Na]⁺.

Production Example 107 Benzyl[4-(4-azidopyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate

Benzyl [4-(4-chloropyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (1.96g) was dissolved in N,N-dimethylformamide (20 ml). Sodium azide (650 mg)was added thereto, followed by stirring at 60° C. for 2 hr. The reactionmixture was allowed to cool to room temperature, then partitionedbetween ethyl acetate and water. The organic layer was washed withbrine, dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure and the resultant residue was purified by silicagel column chromatography (eluent; heptane:ethyl acetate=3:1). Fractionscontaining the target compound were concentrated under reduced pressureand the residue was dried under reduced pressure to provide the titledcompound as white crystals (685 mg, 34%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 5.24 (2H, s), 6.40 (1H, d, J=0.8 Hz),6.93 (1H, brs), 6.99 (1H, dd, J=7.2, 10.0 Hz), 7.30-7.50 (5H, m), 8.13(1H, m), 8.51 (1H, d, J=0.8 Hz).

Production Example 108 4-Amino-6-(4-amino-2,5-difluorophenoxy)pyrimidine

Production Method—1

4-Amino-2,5-difluorophenol (2.15 g) was dissolved in dimethyl sulfoxide(12.5 ml) at room temperature under a nitrogen flow. Potassiumtert-butoxide (1.66 g) was added thereto, followed by stirring at roomtemperature for 5 min. 4-Amino-6-chloropyrimidine (1.55 g) was added,and the resultant mixture was stirred at 100° C. for 18.5 hr under anitrogen flow. The reaction mixture was allowed to cool to roomtemperature, then partitioned between ethyl acetate (100 ml) and a 1Naqueous solution of sodium hydroxide (50 ml). The organic layer waswashed with a 2N aqueous solution of sodium hydroxide (50 ml, 3 times)and brine (50 ml). The solvent was concentrated under reduced pressureand the resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2).Fractions containing the target compound were concentrated under reducedpressure and the residue was dried under reduced pressure to provide thetitled compound as pale yellow powder (271 mg, 9.5%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 3.76 (2H, br), 4.97 (2H, br), 5.94 (1H,d, J=0.8 Hz), 6.60 (1H, dd, J=8.0, 11.2 Hz), 6.87 (1H, dd, J=7.2, 11.2Hz), 8.26 (1H, d, J=0.8 Hz).

ESI-MS (m/z): 239 [M+H]⁺.

Production Method—2

Benzyl [4-(4-aminopyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (561mg) was dissolved in methanol (30 ml). 10% palladium on carbon (321 mg)was added, followed by stirring under a hydrogen atmosphere for 4 hr.The catalyst was filtered off and washed with methanol. The filtrate wasconcentrated under reduced pressure and the residue was dried underreduced pressure to provide the titled compound as pale yellow powder(360 mg, quantitative).

Production Method—3

Benzyl [4-(4-azidopyrimidin-6-yloxy)-2,5-difluorophenyl]carbamate (684mg) was dissolved in methanol (20 ml)-tetrahydrofuran (20 ml). 10%palladium on carbon (366 mg) was added, followed by stirring under ahydrogen atmosphere for 5 hr. The catalyst was filtered off and washedwith methanol. The filtrate was concentrated under reduced pressure andthe residue was dried under reduced pressure to provide the titledcompound as pale yellow powder (373 mg, 91%).

Production Example 109N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of 1-(4-fluorophenylaminocarbonyl)cyclopropanecarboxylicacid (378 mg) in N,N-dimethylformamide (3 ml) were added triethylamine(0.236 ml) and HATU (644 mg) at room temperature under a nitrogenatmosphere, followed by stirring for 30 min. To the resultant mixturewas added 4-amino-6-(4-amino-2,5-difluorophenoxy)pyrimidine (270 mg) inN,N-dimethylformamide (3 ml) at room temperature, followed by stirringfor 6 hr. Triethylamine (0.079 ml) and HATU (215 mg) were added againand the resultant mixture was stirred overnight. The reaction mixturewas partitioned between ethyl acetate (20 ml) and a 1N aqueous solutionof sodium hydroxide (10 ml). The organic layer was washed with a 1Naqueous solution of sodium hydroxide (10 ml, twice) and brine (10 ml),dried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure and the resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; heptane:ethylacetate=1:2 to 1:4). Fractions containing the target compound wereconcentrated under reduced pressure and the residue was dried underreduced pressure to provide the titled compound as pale brown powder(199 mg, 40%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 4.99 (2H, br), 6.00(1H, s), 7.00-7.50 (5H, m), 8.24 (1H, s), 8.26 (1H, m), 8.59 (1H, brs),9.54 (1H, brs).

ESI-MS (m/z): 466 [M+Na]⁺.

Production Example 110 1-(Benzyloxy)-2,3-difluoro-4-nitrobenzene

To a solution of 1,2,3-trifluoro-4-nitrobenzene (5.0 g) and benzylalcohol (2.92 ml) in N,N-dimethylformamide (20 ml) was added potassiumcarbonate (5.85 g), followed by stirring at room temperature for 62 hrand 45 min. To the reaction mixture was added water (80 ml) at 0° C.,followed by stirring at 4° C. for 28 hr. The precipitated crystals werecollected by filtration and washed with water. These crystals were driedunder reduced pressure to provide the titled compound as pale yellowcrystals (6.54 g) which was a mixture of2-(benzyloxy)-3,4-difluoro-1-nitrobenzene.

Production Example 111 4-Amino-2,3-difluorophenol

To a solution of a mixture of 1-(benzyloxy)-2,3-difluoro-4-nitrobenzeneand 2-(benzyloxy)-3,4-difluoro-1-nitrobenzene (6.54 g) in methanol (200ml) was added 10% palladium on carbon (654 mg), followed by stirringunder a hydrogen atmosphere at room temperature for 26 hr and 50 min.The atmosphere in the reaction vessel was replaced with nitrogen to stopthe reaction, and the catalyst was filtered off through Celite. Thefiltrate was concentrated under reduced pressure to provide the titledcompound as a black solid (3.52 g) which was a mixture of6-amino-2,3-difluorophenol.

ESI-MS (m/z): 144 [M−H]⁻.

Production Example 1124-(4-Amino-2,3-difluorophenoxy)pyridine-2-carboxamide

The mixture of 4-amino-2,3-difluorophenol and 6-amino-2,3-difluorophenol(3.52 g) was dissolved in dimethyl sulfoxide (30 ml) under a nitrogenflow, and potassium tert-butoxide (1.49 g) was added at roomtemperature, followed by stirring for 30 min.4-Chloropyridine-2-carboxamide (947 mg) was added thereto, followed bystirring at 80° C. for 6 hr. Then the reaction mixture was stirred at100° C. for 14 hr. The reaction mixture was allowed to cool down to roomtemperature, and a 1N aqueous solution of sodium hydroxide (52.8 ml) wasadded, followed by stirring for 9 hr and 15 min. The reaction mixturewas partitioned between ethyl acetate (300 ml) and water (300 ml). Theaqueous layer was extracted with ethyl acetate (200 ml, twice), then thecombined organic layer was dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure. The resultant residue waspurified by silica gel column chromatography (Fuji Silysia NH, eluent;heptane:ethyl acetate=1:3) and fractions containing the target compoundwere concentrated under reduced pressure. The residue was dried underreduced pressure to provide the titled compound as a pale brown solid(532 mg) which was a mixture of4-(6-amino-2,3-difluorophenoxy)pyridine-2-carboxamide.

ESI-MS (m/z): 264 [M−H]⁻.

Production Example 113N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,3-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxyamide

1-(4-Fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.12 g) wasdissolved in tetrahydrofuran (11 ml) under a nitrogen atmosphere, andN-methylmorpholine (1.21 ml) was added dropwise while cooling in an icewater bath, followed by stirring for 15 min. Then thionyl chloride(0.803 ml) was added at the same temperature, followed by stirring for35 min. The solvent was removed under reduced pressure, the residue wasazeotroped with toluene and dried under reduced pressure. The resultantresidue and the mixture of4-(4-amino-2,3-difluorophenoxy)pyridine-2-carboxamide and4-(6-amino-2,3-difluorophenoxy)pyridine-2-carboxamide (532 mg) weredissolved in tetrahydrofuran (12 ml) under a nitrogen atmosphere. ThenN-methylmorpholine (1.21 ml) was added at room temperature, followed bystirring for 28 hr and 20 min. The reaction was stopped by adding a 1Naqueous solution of sodium hydroxide (10 ml), and the reaction mixturewas partitioned between ethyl acetate (100 ml) and water (20 ml). Theorganic layer was washed with water (100 ml) and brine (50 ml), driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2,then ethyl acetate), and fractions containing the target compound wereconcentrated under reduced pressure. The residue was dried under reducedpressure to provide the titled compound as a pale brown solid (294.7mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.63-1.82 (4H, m), 5.53-5.56 (2H, m),7.03-7.08 (3H, m), 7.46-7.49 (2H, m), 7.66 (1H, d, J=2.8 Hz), 7.80-7.88(1H, m), 8.03-8.08 (1H, m), 8.46 (1H, d, J=5.2 Hz), 8.48 (1H, brs),9.78-9.81 (1H, m).

ESI-MS (m/z): 493 [M+Na]⁺

Production Example 114N-{4-[(2-Aminopyridin-4-yl)oxy]-2,3-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-(4-{[2-(Aminocarbonyl)pyridin-4-yl]oxy}-2,3-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(295 mg) was dissolved in N,N-dimethylformamide (4 ml). Water (0.0563ml), [bis(trifluoroacetoxy)iodo]benzene (536 mg) and pyridine (0.303 ml)were added thereto at room temperature in this order, followed bystirring for 25 hr and 10 min. The reaction was stopped by adding a 1Naqueous solution of sodium hydroxide (9 ml), and the reaction mixturewas partitioned between ethyl acetate (30 ml) and water (10 ml). Theorganic layer was washed with water (30 ml) in twice, brine and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:3), andfractions containing the target compound were concentrated under reducedpressure. The residue was dried under reduced pressure to provide thetitled compound as a pale yellow solid (168.4 mg, 61%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.67-1.80 (4H, m), 3.74 (2H, m), 4.54(2H, brs), 5.96 (1H, d, J=2.4 Hz), 6.28 (1H, dd, J=2.4, 5.6 Hz),6.92-7.02 (1H, m), 7.02-7.10 (2H, m), 7.45-7.50 (1H, m), 7.96 (1H, d,J=5.6 Hz), 8.42 (1H, brs), 9.75 (1H, brs).

ESI-MS (m/z): 443[M+H]⁺.

Example 61N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl]oxy}-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(1.5 g) was dissolved in tetrahydrofuran (15 ml) under a nitrogenatmosphere, and triethylamine (0.987 ml) and phenyl chloroformate (0.978ml) were added dropwise at room temperature in this order, followed bystirring for 30 min. The reaction mixture was stirred after addition ofethyl acetate and a saturated aqueous solution of sodiumhydrogencarbonate. The organic layer was separated, washed with brine,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The residue was dissolved inN,N-dimethylformamide (7.5 ml). Triethylamine (4.92 ml) and azetidinehydrochloride (1.33 g) were added at room temperature, followed bystirring for 7.5 hr. The reaction mixture was partitioned between ethylacetate and a saturated aqueous solution of sodium hydrogencarbonate.The organic layer was washed with water (three times) and brine in thisorder, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. To the resultant residue were addedethyl acetate (5 ml) and heptane (5 ml) to precipitate a solid. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (1.29 g, 72%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.31 (2H, m), 4.11(4H, m), 6.60 (1H, dd, J=2.4, 5.6 Hz), 6.91-7.52 (7H, m), 7.74 (1H, d,J=2.4 Hz), 8.01 (1H, d, J=5.6 Hz), 8.24 (1H, m), 8.96 (1H, brs), 9.12(1H, brs).

ESI-MS (m/z): 530 [M+Na]⁺.

Example 62N-(4-Fluorophenyl)-N′-[2-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide

To a solution of roughly purified[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was addedpyrrolidine (0.100 ml) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure. To the resultant residue was addeddiethyl ether:heptane=1:2 to precipitate a solid. The solvent wasconcentrated under reduced pressure, and the residue was dried underreduced pressure to provide the titled compound as white powder (17.4mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 1.90-2.04 (4H, m),3.44-3.60 (4H, m), 6.63 (1H, dd, J=2.4, 5.6 Hz), 6.90-7.55 (7H, m), 7.88(1H, m), 8.00 (1H, d, J=5.6 Hz), 8.28 (1H, m), 9.00-9.10 (2H, m).

ESI-MS (m/z): 544 [M+Na]⁺.

Example 63N-[2-Fluoro-4-({2-[(morpholin-4-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of roughly purified[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (150 mg) in N,N-dimethylformamide (1.5 ml) was addedmorpholine (0.100 ml) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure. To the resultant residue was addeddiethyl ether:heptane=1:2 to precipitate a solid. The solvent wasconcentrated under reduced pressure, and the residue was dried underreduced pressure to provide the titled compound as white powder (12.2mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 3.60-3.80 (8H, m),6.78 (1H, dd, J=2.4, 5.6 Hz), 6.90-7.55 (7H, m), 7.91 (1H, d, J=5.6 Hz),8.06 (1H, m), 8.40 (1H, m), 8.51 (1H, brs), 9.70 (1H, brs).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 64N-{2-Fluoro-4-[(2-{[(1-methylpiperazin-4-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of roughly purified[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (200 mg) in N,N-dimethylformamide (2.0 ml) was added1-methylpiperazine (0.170 ml) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. To the resultant residue wasadded diethyl ether:heptane=1:2 to precipitate a solid. The solvent wasconcentrated under reduced pressure, and the residue was dried underreduced pressure to provide the titled compound as white powder (27.0mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.65 (3H, brs),2.80-3.00 (4H, m), 3.80-4.00 (4H, m), 6.65 (1H, m), 6.90-7.55 (7H, m),7.68 (1H, m), 8.00 (1H, m), 8.29 (1H, m), 8.79 (1H, brs), 9.35 (1H,brs).

ESI-MS (m/z): 573 [M+Na]⁺.

Example 65N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) were addedtriethylamine (0.130 ml) and azetidine hydrochloride (60 mg) at roomtemperature, followed by stirring for 3 hr. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate andbrine in this order, and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (eluent; ethylacetate). Fractions containing the target compound were concentratedunder reduced pressure. To the resultant residue was added diethylether:heptane=1:2 to precipitate a solid. The solvent was concentratedunder reduced pressure, and residue was dried under reduced pressure toprovide the titled compound as white powder (41.7 mg, 69%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.30 (2H, m), 4.10(4H, m), 6.63 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (7H, m), 7.67 (1H, m),7.70 (1H, dd, J=2.4, 12.0 Hz), 8.01 (1H, d, J=5.6 Hz), 8.60 (1H, brs),9.64 (1H, brs).

ESI-MS (m/z): 530 [M+Na]⁺.

Example 66N-(4-Fluorophenyl)-N′-[3-fluoro-4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1′-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) was addedpyrrolidine (0.050 ml) at room temperature, followed by stirring for 3hr. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate and brine in this order, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (eluent; ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure. To the resultantresidue was added diethyl ether:heptane=1:2 to precipitate a solid. Thesolvent was concentrated under reduced pressure, and the residue wasdried under reduced pressure to provide the titled compound as whitepowder (45.9 mg, 73%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 1.86-2.04 (4H, m),3.40-3.52 (4H, m), 6.63 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (7H, m),7.65-7.75 (2H, m), 8.01 (1H, d, J=5.6 Hz), 8.68 (1H, brs), 9.62 (1H,brs).

ESI-MS (m/z): 544 [M+Na]⁺.

Example 67N-[3-Fluoro-4-({2-[(morpholin-4-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)-cyclopropane-1,1-dicarboxamide

To a solution of[4-(2-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (80 mg) in N,N-dimethylformamide (1.0 ml) was addedmorpholine (0.055 ml) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate). Fractions containing thetarget compound were concentrated under reduced pressure. To theresultant residue was added diethyl ether:heptane=1:2 to precipitate asolid. The solvent was concentrated under reduced pressure to providethe titled compound as white powder (52.3 mg, 81%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 3.44-3.54 (4H, m),3.66-3.76 (4H, m), 6.58 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (7H, m), 7.58(1H, m), 7.69 (1H, m), 8.03 (1H, d, J=5.6 Hz), 8.51 (1H, brs), 9.64 (1H,brs).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 68N-(4-Fluorophenyl)-N′-[4-({2-[(morpholin-4-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide

Morpholine-4-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (121mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (92.0 mg)were dissolved in N,N-dimethylformamide (4 ml), anddiisopropylethylamine (0.358 ml) and HBTU(O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate;213 mg) were added under a nitrogen atmosphere at room temperature,followed by stirring for 4 hr. The reaction mixture was partitionedafter addition of ethyl acetate (50 ml) and a saturated aqueous solutionof sodium hydrogencarbonate (20 ml). The separated organic layer waswashed with a saturated aqueous solution of sodium hydrogencarbonate (30ml) and brine (30 ml), and dried over anhydrous sodium sulfate. Thesolvent was removed under reduced pressure, and the resultant residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=1:7, then ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure, and to the residue(131.9 mg) were added tert-butyl methyl ether (4 ml) and heptane (4 ml)to suspend a solid. The solid was collected by filtration, and driedunder aeration to provide a titled compound as pale yellow powder (107.1mg, 55.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.44-2.04 (4H, m), 3.53 (4H, m), 3.72(4H, m), 6.63 (1H, m), 7.00-7.15 (5H, m), 7.40-7.53 (2H, m), 7.53-7.62(3H, m), 7.99 (1H, m), 8.94 (1H, brs), 9.07 (1H, brs).

ESI-MS (m/z): 542 [M+Na]⁺.

Example 69N-(4-Fluorophenyl)-N′-[4-({2-[(pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide

Pyrrolidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (112mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (87.4 mg)were dissolved in N,N-dimethylformamide (4 ml), anddiisopropylethylamine (0.341 ml) and HBTU (203 mg) were added under anitrogen atmosphere at room temperature, followed by stirring for 3 hr.The reaction mixture was partitioned after addition of ethyl acetate (50ml) and a saturated aqueous solution of sodium hydrogencarbonate (20ml). The separated organic layer was washed with a saturated aqueoussolution of sodium hydrogencarbonate (30 ml) and brine (30 ml), anddried over anhydrous sodium sulfate. The solvent was removed underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; heptane:ethyl acetate=1:7, then ethylacetate). Fractions containing the target compound were concentratedunder reduced pressure, and to the residue (133.0 mg) were addedtert-butyl methyl ether (4 ml) and heptane (4 ml) to suspend a solid.The solid was collected by filtration and dried under aeration toprovide the titled compound as pale yellow powder (111.1 mg, 62.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.78-1.84 (4H, m), 1.95 (4H, m), 3.47(4H, m), 6.63 (1H, m), 6.95-7.10 (5H, m), 7.40-7.53 (2H, m), 7.57 (2H,m), 7.66 (1H, brs), 7.98 (1H, m), 8.98 (1H, brs), 9.11 (1H, brs).

ESI-MS (m/z): 526 [M+Na]⁺.

Example 70N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

Azetidine-1-carboxylic acid [4-(4-aminophenoxy)pyridin-2-yl]amide (108mg) and 1-(4-fluorophenylcarbamoyl)cyclopropanecarboxylic acid (93.1 mg)were dissolved in N,N-dimethylformamide (4 ml), anddiisopropylethylamine (0.363 ml) and HBTU (216 mg) were added under anitrogen atmosphere at room temperature, followed by 3 hr. The reactionmixture was partitioned after addition of ethyl acetate (50 ml) and asaturated aqueous solution of sodium hydrogencarbonate (20 ml). Theseparated organic layer was washed with a saturated aqueous solution ofsodium hydrogencarbonate (30 ml) and brine (30 ml), and dried overanhydrous sodium sulfate. The solvent was removed under reducedpressure, and the resultant residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=1:7, then ethyl acetate).Fractions containing the target compound were concentrated under reducedpressure, and to the residue (106.2 mg) were added tert-butyl methylether (4 ml) and heptane (4 ml) to suspend a solid. The solid wascollected by filtration, and dried under aeration to provide the roughlypurified titled compound as pale yellow powder (87.5 mg). This waspurified by silica gel column chromatography (eluent; heptane:ethylacetate=1:7, then ethyl acetate). Fractions containing the targetcompound were concentrated under reduced pressure, and to the residuewere added tert-butyl methyl ether (4 ml) and heptane (2 ml) to suspenda solid. The solid was collected by filtration, and dried under aerationto provide white powder. The powder obtained by filtration and thefiltrate were combined, and purified by LC-MS. The solution containingTFA, acetonitrile and water was concentrated under reduced pressure, andto the residue was added a saturated aqueous solution of sodiumhydrogencarbonate (50 ml), followed by stirring. The solvent was removedunder reduced pressure, and the residue was partitioned after additionof ethyl acetate (100 ml). The organic layer was washed with a saturatedaqueous solution of sodium hydrogencarbonate (50 ml) and brine (50 ml)in this order, and dried over anhydrous sodium sulfate. The solvent wasremoved under reduced pressure, and to the residue were added tert-butylmethyl ether and heptane to suspend a solid. The solid was collected byfiltration, and derided under aeration to provide the titled compound asa white powder (16.3 mg, 8.79%)

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.30-1.80 (4H, m), 2.30 (2H, m), 4.12(4H, m), 6.62 (1H, m), 6.95-7.14 (5H, m), 7.48 (2H, m), 7.59 (2H, m),7.73 (1H, brs), 7.96 (1H, m), 8.98 (1H, brs), 9.07 (1H, brs).

ESI-MS (m/z): 512 [M+Na]⁺.

Example 71N-(4-Fluorophenyl)-N′-{2-fluoro-4-[(2-{[(4-piperazin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide

To a solution of a crude product of[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamicacid phenyl ester (300 mg) in N,N-dimethylformamide (4.5 ml) were addedbenzyl 4-(piperidin-4-yl)piperazine-1-carboxylate (684 mg) andtriethylamine (0.629 ml), followed by stirring at room temperature for20.5 hr. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with brine, and dried over anhydroussodium sulfate. The solvent was removed to provide a crude product ofbenzyl4-{1-[4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-ylcarbamoyl]piperidin-4-yl}piperazine-1-carboxylateas a pale yellow oil (501 mg). This was dissolved in ethanol (10 ml) andN,N-dimethylformamide (5.0 ml). 1,4-cyclohexadiene (0.633 ml) and 10%palladium on carbon (144 mg) were added thereto, followed by stirring at65° C. for 1.5 hr. The reaction mixture was allowed to cool down to roomtemperature. The catalyst was removed by filtration, and the filtratewas concentrated. The residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, ethylacetate:methanol=10:1, then 5:1). Fractions containing the targetcompound were concentrated to give the residue (56.3 mg). The residuewas purified by LC-MS. Fractions containing the target compound wereconcentrated, which were partitioned between ethyl acetate and asaturated aqueous solution of sodium hydrogencarbonate. The organiclayer was dried over anhydrous sodium sulfate. The solvent was removed,and to the residue was added diethyl ether to suspend a solid. This wascollected by filtration, and dried under aeration to provide the titledcompound as pale yellow powder (12.7 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.48 (2H, m), 1.66-1.75 (4H, m), 1.85(2H, m), 2.47-3.16 (12H, m), 4.13 (2H, m), 6.56 (1H, m), 6.91 (2H, m),7.04 (2H, m), 7.40 (1H, m), 7.50 (2H, dd, J=4.8, 8.8 Hz), 7.60 (1H, s),8.06 (1H, d, J=5.6 Hz), 8.19 (1H, m), 8.98 (1H, s), 9.16 (1H, s).

ESI-MS (m/z): 620 [M+H]⁺.

Example 72N-{2-Fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(250 mg) was dissolved in tetrahydrofuran (6.0 ml) under a nitrogenatmosphere, and triethylamine (0.247 ml) and phenyl chloroformate (0.163ml) were added dropwise at room temperature in this order, followed bystirring for 1 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(6.0 ml). This solution was added to a mixture of 3-hydroxyazetidinehydrochloride (259 mg) and triethylamine (0.822 ml), followed bystirring at room temperature for 14.25 hr. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a 1N aqueous solution of sodium hydroxide, water and brinein this order, and dried over anhydrous sodium sulfate. The solvent wasremoved and the residue was purified by silica gel column chromatography(Fuji Silysia NH, eluent; heptane:ethyl acetate=1:2, ethyl acetate,ethyl acetate:methanol=30:1, then 10:1). Fractions containing the targetcompound were concentrated. To the resultant residue was added diethylether:heptane=1:2 to suspend a solid. The solid was collected byfiltration and washed with heptane. This was dried under aeration toprovide white powder (198 mg). This was suspended in 2-propanol (2 ml).Insoluble matter was removed by filtration and washed with 2-propanol.This was dried under aeration to provide white powder (178 mg). This wasagain suspended in 2-propanol (2 ml). This was collected by filtration,washed with 2-propanol, and dried under aeration to provide the titledcompound as white powder (144.2 mg, 46.7%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 2.27 (1H, m), 3.92(2H, dd, J=4.2, 9.8 Hz), 4.28 (2H, dd, J=6.6, 9.8 Hz), 4.69 (1H, m),6.57 (1H, dd, J=2.0, 5.6 Hz), 6.79 (1H, s), 6.91 (2H, m), 7.04 (2H, m),7.50 (2H, dd, J=4.8, 9.2 Hz), 7.64 (1H, d, J=2.0 Hz), 8.06 (1H, d, J=5.6Hz), 8.19 (1H, m), 8.82 (1H, s), 9.26 (1H, s).

ESI-MS (m/z): 524 [M+H]⁺, 546 [M+Na]⁺.

Example 73N-[4-({2-[(1,3′-Biazetidin-1′-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

To a suspension of 3-(azetidin-1-yl)azetidine dihydrochloride

-   (111 mg) in N,N-dimethylformamide (1.5 ml) was added triethylamine    (0.167 ml), followed by stirring at room temperature for 15 min. A    crude product of    [4-(3-fluoro-4-{[1-(4-fluorophenylcarbamoyl)cyclopropanecarbonyl]amino}phenoxy)pyridin-2-yl]-N-(phenoxycarbonyl)carbamic    acid phenyl ester (100 mg) was added thereto, followed by stirring    at room temperature for 25 hr. The reaction mixture was partitioned    between ethyl acetate and water. The organic layer was washed with    brine, and dried over anhydrous sodium sulfate. This was    concentrated and the residue was purified by LC-MS. Fractions    containing the target compound were concentrated, and the residue    was partitioned between ethyl acetate and a saturated aqueous    solution of sodium hydrogencarbonate. The organic layer was washed    with brine, and dried over anhydrous sodium sulfate. The solvent was    removed, and to the resultant solid (31.5 mg) was added diethyl    ether (2 ml) to suspend. This was collected by filtration and washed    with diethyl ether. This was dried under aeration to provide the    titled compound as colorless powder (5.0 mg).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.65-1.75 (4H, m), 2.17 (2H, m), 3.33(4H, m), 3.48 (1H, m), 3.88 (2H, m), 4.06 (2H, m), 6.58 (1H, m), 6.92(2H, m), 7.04 (2H, m), 7.11 (1H, m), 7.51 (2H, dd, J=4.8, 9.2 Hz), 7.66(1H, s), 8.05 (1H, d, J=6.0 Hz), 8.22 (1H, m), 8.84 (1H, s), 9.22 (1H,s).

ESI-MS (m/z): 585 [M+Na]⁺.

Example 75 N-(2-Fluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-ylcarbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogenatmosphere, and triethylamine (0.074 ml) and phenyl chloroformate(0.0488 ml) were added dropwise in this order at room temperature,followed by stirring for 1 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(1.8 ml). This solution was added to a mixture of a crude product of3-(hydroxymethyl)azetidine trifluoroacetate (209.8 mg, corresponds to0.671 mmol) and triethylamine (0.658 ml), followed by stirring at roomtemperature for 12 hr. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was removed and the residuewas purified by silica gel column chromatography (eluent; ethyl acetate,ethyl acetate:methanol=50:1, 20:1, then 10:1). Fractions containing thetarget compound were concentrated. To the resultant residue (36.9 mg)was added diethyl ether:heptane=1:2 to suspend a solid. The solid wascollected by filtration and washed with heptane. This was dried underaeration to provide the titled compound as white powder (22.0 mg,23.1%).

¹H-NMR Spectrum (CDCl₃):δ (ppm): 1.64-1.75 (4H, m), 2.82 (1H, m), 3.80(2H, d, J=6.0 Hz), 3.85 (2H, dd, J=5.6, 8.0 Hz), 4.11 (2H, m), 6.57 (1H,dd, J=2.4, 6.0 Hz), 6.89-7.00 (2H, m), 7.03 (2H, m), 7.12 (1H, m),7.47-7.52 (2H, m), 7.65 (1H, d, J=2.4 Hz), 8.04 (1H, d, J=6.0 Hz), 8.17(1H, m), 8.91 (1H, s), 9.27 (1H, s).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 76N-(4-{[2-({[3-(Dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (2.4 ml) under a nitrogenatmosphere, and triethylamine (0.0987 ml) and phenyl chloroformate(0.0651 ml) were added dropwise at room temperature in this order,followed by stirring for 1 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(2.4 ml). This solution was added to a mixture of a crude product of3-(dimethylamino)azetidine ditrifluoroacetate (592 mg, corresponds to0.944 mmol) and triethylamine (0.658 ml), followed by stirring at roomtemperature for 12 hr. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was removed and the residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; ethyl acetate=1:2, ethyl acetate, then ethylacetate:methanol=30:1). Fractions containing the target compound wereconcentrated. To the resultant residue (71.3 mg) was added diethylether:heptane=1:2 to suspend a solid. The solid was collected byfiltration and washed with heptane. This was dried under aeration toprovide the titled compound as white powder (52.4 mg, 40.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 2.18 (6H, s), 3.13(1H, m), 3.90 (2H, m), 4.04 (2H, m), 6.56 (1H, m), 6.86 (1H, brs), 6.91(2H, m), 7.04 (2H, m), 7.49-7.52 (2H, dd, J=4.8, 8.8 Hz), 7.65 (1H, d,J=2.0 Hz), 8.05 (1H, d, J=5.6 Hz), 8.20 (1H, m), 8.81 (1H, s), 9.26 (1H,s).

ESI-MS (m/z): 573 [M+Na]⁺.

Example 77N-[4-({2-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (2.4 ml) under a nitrogenatmosphere, and triethylamine (0.0987 ml) and phenyl chloroformate(0.0651 ml) were added dropwise at room temperature in this order,followed by stirring for 1 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(2.4 ml). This solution was added to a mixture of a crude product of3-(dimethylaminomethyl)azetidine ditrifluoroacetate (469 mg, correspondsto 0.826 mmol), and triethylamine (0.658 ml), followed by stirring atroom temperature for 17.5 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was removed, and theresidue was purified by silica gel column chromatography (Fuji SilysiaNH, eluent; heptane:ethyl acetate=1:2, ethyl acetate, ethylacetate:methanol=30:1, then 10:1). Fractions containing the targetcompound were concentrated. To the resultant residue (77.9 mg) wereadded diethyl ether:heptane=1:2 to suspend a solid. The solid wascollected by filtration and washed with heptane. This was dried underaeration to provide the titled compound as white powder (70.9 mg,53.2%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.75 (4H, m), 2.22 (6H, s), 2.53(2H, d, J=7.2 Hz), 2.80 (1H, m), 3.71 (2H, m), 4.13 (2H, m), 6.56 (1H,m), 6.79 (1H, s), 6.91 (2H, m), 7.03 (2H, m), 7.50 (2H, dd, J=4.8, 9.2Hz), 7.65 (1H, m), 8.06 (1H, d, J=5.6 Hz), 8.20 (1H, m), 8.82 (1H, s),9.25 (1H, s).

ESI-MS (m/z): 565 [M+H]⁺.

Example 78N-[2-Fluoro-4-[(2-{[(3-methoxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogenatmosphere, and triethylamine (0.074 ml) and phenyl chloroformate(0.0488 ml) were added dropwise in this order at room temperature,followed by stirring for 1 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(1.8 ml). This solution was added to a mixture of a crude product of3-methoxyazetidine trifluoroacetate (209.8 mg, corresponds to 0.671mmol) and triethylamine (0.450 ml), followed by stirring at roomtemperature for 13 hr. The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=1:2, ethyl acetate, ethyl acetate:methanol=50:1, then 20:1).Fractions containing the target compound were concentrated. To theresultant residue was added diethyl ether:heptane=1:2 to suspend asolid. The solid was collected by filtration and washed with heptane.This was dried under aeration to provide the titled compound as whitepowder (46.5 mg, 48.9%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.64-1.76 (4H, m), 3.31 (3H, s), 3.94(2H, m), 4.20 (3H, m), 6.56 (1H, dd, J=2.4, 5.6 Hz), 6.91 (3H, m), 7.03(2H, m), 7.50 (2H, m), 7.64 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz),8.19 (1H, m), 8.90 (1H, s), 9.25 (1H, s).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 79N-[3-Fluoro-4-[(2-{[3-methoxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(75 mg) was dissolved in tetrahydrofuran (1.8 ml) under a nitrogenatmosphere, and triethylamine (0.074 ml) and phenyl chloroformate(0.0488 ml) were added dropwise at room temperature in this order,followed by stirring for 1 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was washed with a 1Naqueous solution of sodium hydroxide, water and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(1.8 ml). This solution was added to a mixture of a crude product of3-methoxyazetidine trifluoroacetate (corresponds to 0.671 mmol) andtriethylamine (0.247 ml), followed by stirring at room temperatureovernight (for 11 hr). The reaction mixture was partitioned betweenethyl acetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was removed, and the residuewas purified by silica gel column chromatography (eluent; heptane:ethylacetate=1:2, ethyl acetate, then ethyl acetate:methanol=50:1). Fractionscontaining the target compound were concentrated. To the resultantresidue (64.2 mg) was added diethyl ether:heptane=1:2 to suspend asolid. The solid was collected by filtration and washed with heptane.This was dried under aeration provide the titled compound as whitepowder (54.6 mg, 57.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.63-1.73 (4H, m), 3.30 (3H, s), 3.92(2H, m), 4.20 (3H, m), 6.59 (1H, dd, J=2.4, 5.6 Hz), 6.86 (1H, brs),7.04 (2H, m), 7.11 (1H, m), 7.19 (1H, m), 7.47 (2H, dd, J=4.8, 9.2 Hz),7.59 (1H, d, J=2.4 Hz), 7.68 (1H, dd, J=2.8, 8.0 Hz), 8.04 (1H, d, J=5.6Hz), 8.62 (1H, s), 9.53 (1H, s).

ESI-MS (m/z): 560 [M+H]⁺.

Example 80N-{3-Fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(250 mg) was dissolved in tetrahydrofuran (6.0 ml) under a nitrogenatmosphere, and triethylamine (0.247 ml) and phenyl chloroformate (0.163ml) were added dropwise in this order at room temperature, followed bystirring for 30 min. The reaction mixture was stirred after addition ofethyl acetate and water. The organic layer was separated, washed with a1N aqueous solution of sodium hydroxide, water and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The residue was dissolved inN,N-dimethylformamide (6.0 ml). Triethylamine (0.822 ml) and3-hydroxyazetidine hydrochloride (259 mg) were added at roomtemperature, followed by stirring overnight. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer waswashed with a 1N aqueous solution of sodium hydroxide, water and brinein this order, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (eluent; ethyl acetate, ethylacetate:methanol=95:5, 9:1). Fractions containing the target compoundwere concentrated under reduced pressure. To the resultant residue wasadded tert-butyl methyl ether:heptane=1:2 to precipitate a solid. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (173.7 mg, 56%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 3.96 (2H, dd, J=4.0,9.2 Hz), 4.30 (2H, dd, J=6.8, 9.2 Hz), 4.67 (1H, m), 6.66 (1H, dd,J=2.4, 5.6 Hz), 7.00-7.50 (7H, m), 7.66 (1H, brs), 7.71 (1H, dd, J=2.4,12.0 Hz), 8.00 (1H, d, J=5.6 Hz), 8.61 (1H, brs), 9.66 (1H, brs).

ESI-MS (m/z): 546 [M+Na]⁺.

Example 81N-(3-Fluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(297 mg) was dissolved in tetrahydrofuran (8.0 ml) under a nitrogenatmosphere, and triethylamine (0.293 ml) and phenyl chloroformate (0.193ml) were added dropwise at room temperature in this order, followed bystirring for 1 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(8.0 ml). This solution was added to a mixture of a crude product of3-(hydroxymethyl)azetidine trifluoroacetate (corresponds to 2.58 mmol)and triethylamine (2.0 ml), followed by stirring at room temperature for11 hr. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was washed with a 1N aqueous solution of sodiumhydroxide, water and brine in this order, and dried over anhydroussodium sulfate. The solvent was removed, and the residue was purified bysilica gel column chromatography (eluent; heptane:ethyl acetate=1:2,ethyl acetate, ethyl acetate:methanol=50:1, then 20:1). Fractionscontaining the target compound were concentrated. To the resultantresidue (159.4 mg) was added diethyl ether:heptane=1:2 to suspend asolid. The solid was collected by filtration and washed with heptane.This was dried under aeration to provide the titled compound as whitepowder (143.2 mg, 38.1%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.59-1.67 (4H, m), 2.77 (1H, m), 3.74(2H, d, J=5.6 Hz), 3.84 (2H, dd, J=5.2, 8.0 Hz), 4.05 (2H, m), 6.70 (1H,dd, J=2.0, 5.6 Hz), 6.98-7.06 (4H, m), 7.18 (1H, m), 7.46-7.94 (2H, m),7.55 (1H, d, J=2.0 Hz), 7.64 (1H, dd, J=2.4, 8.4 Hz), 8.06 (1H, d, J=5.6Hz), 9.21 (1H, s), 9.65 (1H, s).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 82N-[2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0658 ml) and phenyl chloroformate(0.0652 ml) were added while stirring and cooling in an ice water bath,followed by stirring at the same temperature for 1 hr. The reactionmixture was partitioned between ethyl acetate (30 ml) and a saturatedaqueous solution of sodium hydrogencarbonate (20 ml). The separatedorganic layer was washed with brine (30 ml), and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure. To theresidue was added N,N-dimethylformamide (2.5 ml), and4-hydroxypiperidine (95.5 mg) and triethylamine (0.132 ml) were addedthereto, followed by stirring at room temperature overnight. Thereaction mixture was partitioned after addition of ethyl acetate (30 ml)and a saturated aqueous solution of sodium hydrogencarbonate (20 ml).The separated organic layer was washed with brine (30 ml), and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:5,ethyl acetate, then ethyl acetate:methanol=95:5). Crude fractionscontaining the target compound were concentrated under reduced pressure,and the residue was purified by silica gel column chromatography(eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure, and to the residue were addedtert-butyl methyl ether (2 ml) and heptane (4 ml) to suspend a solid.The solid was collected by filtration and dried under aeration toprovide the titled compound as white powder (113.6 mg, 87.3%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.35-1.82 (7H, m), 1.82-2.00 (2H, m),3.28 (2H, m), 3.76-3.90 (2H, m), 3.94 (1H, m), 6.59 (1H, m), 6.93 (2H,m), 7.04 (2H, m), 7.26 (1H, m), 7.40-7.60 (2H, m), 7.70 (1H, brs), 8.03(1H, d, J=6.0 Hz), 8.23 (1H, m), 9.01 (1H, brs), 9.09 (1H, brs).

ESI-MS (m/z): 574 [M+Na]⁺.

Example 83N-(2-Fluoro-4-{[2-({[4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0724 ml) and phenyl chloroformate(0.0652 ml) were added while stirring and cooling in an ice water bath,followed by stirring at the same temperature for 1 hr. The reactionmixture was partitioned between ethyl acetate (30 ml) and a saturatedaqueous solution of sodium hydrogencarbonate (20 ml). The separatedorganic layer was washed with brine (30 ml), and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure. To theresidue was added N,N-dimethylformamide (2.5 ml), and4-piperidinemethanol (109 mg) and triethylamine (0.132 ml) were added,followed by stirring at room temperature overnight. The reaction mixturewas partitioned between ethyl acetate (30 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with brine (30 ml), and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure, and the residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; heptane:ethyl acetate=1:5, ethyl acetate, then ethylacetate:methanol=95:5). Crude fractions containing the target compoundwere concentrated under reduced pressure, and the residue was purifiedby silica gel column chromatography (eluent; heptane:ethyl acetate=1:5,ethyl acetate, then ethyl acetate:methanol=95:5). Fractions containingthe target compound were concentrated under reduced pressure, and to theresidue were added tert-butyl methyl ether (2 ml) and heptane (4 ml) tosuspend a solid. The solid was collected by filtration and dried underaeration to provide the titled compound as white powder (98.1 mg,73.5%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-1.77 (8H, m), 1.82 (2H, m), 2.90(2H, m), 3.52 (2H, m), 4.19 (2H, m), 6.59 (1H, dd, J=2.4, 6.0 Hz), 6.93(2H, m), 7.04 (2H, m), 7.26 (1H, m), 7.50 (2H, m), 7.73 (1H, brs), 8.02(1H, d, J=6.0 Hz), 8.23 (1H, m), 9.01 (1H, brs), 9.09 (1H, brs).

ESI-MS (m/z): 588 [M+Na]⁺.

Example 84N-[3-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-111-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (4.0 ml) under a nitrogenatmosphere, and triethylamine (0.148 ml) and phenyl chloroformate (0.098ml) were added dropwise in this order at room temperature, followed bystirring for 10 min. The reaction mixture was stirred after addition ofethyl acetate and water. The organic layer was separated, washed with a1N aqueous solution of sodium hydroxide, water and brine, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (4.0 ml).4-Hydroxypiperidine (146 mg) was added at room temperature, followed bystirring for 2 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure. To the resultant residue was addedtert-butyl methyl ether:heptane=1:2 to precipitate a solid. The solidwas collected by filtration and dried under aeration to provide thetitled compound as white powder (138.0 mg, 71%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.00 (8H, m), 3.25 (2H, m),3.80-4.00 (3H, m), 6.60 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (7H, m), 7.64(1H, brs), 7.71 (1H, dd, J=2.4, 12.0 Hz), 8.01 (1H, brs), 8.53 (1H, m),9.65 (1H, brs).

ESI-MS (m/z): 552 [M+H]⁺.

Example 85N-(3-Fluoro-4-{[2-({[-4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (4.0 ml) under a nitrogenatmosphere, and triethylamine (0.148 ml) and phenyl chloroformate (0.098ml) were added dropwise at room temperature in this order, followed bystirring for 10 min. The reaction mixture was stirred after addition ofethyl acetate and water. The organic layer was separated, washed with a1N aqueous solution of sodium hydroxide, water and brine, and dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (4.0 ml).4-Piperidinemethanol (163 mg) was added at room temperature, followed bystirring for 2 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (eluent; ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated. To the resultant residue was added tert-butyl methylether:heptane=1:2 to precipitate a solid. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (143.7 mg, 72%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.00 (9H, m), 2.89 (2H, m), 3.51(2H, m), 4.18 (2H, m), 6.62 (1H, dd, J=2.4, 5.6 Hz), 7.00-7.50 (7H, m),7.60-7.80 (2H, m), 8.01 (1H, d, J=5.6 Hz), 8.49 (1H, brs), 9.69 (1H,brs).

ESI-MS (m/z): 566 [M+H]⁺.

Example 86N-(3-Fluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogenatmosphere, and triethylamine (0.181 ml) and phenyl chloroformate (0.163ml) were added while stirring and cooling in an ice water bath, followedby stirring at the same temperature for 15 min. The reaction mixture waspartitioned between ethyl acetate (30 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with brine (30 ml), and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. To the residuewas added N,N-dimethylformamide (1.5 ml), and (R)-(−)-3-pyrrolidinolhydrochloride (175 mg) and triethylamine (0.198 ml) were added, followedby stirring at room temperature for 5 hr. The reaction mixture waspartitioned after addition of ethyl acetate (30 ml) and a saturatedaqueous solution of sodium hydrogencarbonate (20 ml). The separatedorganic layer was washed with brine (30 ml), and dried over anhydroussodium sulfate. The solvent was removed under reduced pressure, and theresidue was purified by silica gel column chromatography (eluent;heptane:ethyl acetate=1:5, ethyl acetate, then ethylacetate:methanol=95:5). Fractions containing the target compound wereconcentrated under reduced pressure, and to the residue (130 mg) wereadded tert-butyl methyl ether (2 ml) and heptane (2 ml) to suspend asolid. The solid was collected by filtration and dried under aeration toprovide the titled compound as white powder (123.6 mg, 65.0%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.30-2.00 (7H, m), 3.45-3.80 (4H, m),4.50 (1H, m), 6.67 (1H, dd, J=2.4, 6.0 Hz), 6.90-7.15 (4H, m), 7.20 (1H,m), 7.40-7.60 (2H, m), 7.60-7.80 (2H, m), 8.04 (1H, d, J=6.0 Hz), 8.95(1H, brs), 9.66 (1H, brs).

ESI-MS (m/z):538[M+H]⁺, 560[M+Na]⁺.

Example 87N-(2-Fluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogenatmosphere, and triethylamine (0.181 ml) and phenyl chloroformate (0.163ml) were added while stirring and cooling in an ice water bath, followedby stirring at the same temperature for 15 min. The reaction mixture waspartitioned between ethyl acetate (30 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with brine (30 ml), and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. To the residuewas added N,N-dimethylformamide (1.5 ml), and then(R)-(−)-3-pyrrolidinol hydrochloride (175 mg) and triethylamine (0.198ml) were added, followed by stirring at room temperature for 5 hr. Thereaction mixture was partitioned after addition of ethyl acetate (30 ml)and a saturated aqueous solution of sodium hydrogencarbonate (20 ml).The separated organic layer was washed with brine (30 ml), and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate 1:5, ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure, and to the residue (150 mg)were added tert-butyl methyl ether (2 ml) and heptane (2 ml) to suspenda solid. The solid was collected by filtration, and dried under aerationto provide the titled compound as white powder (141.6 mg, 74.4%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.40-2.00 (7H, m), 3.50-3.70 (4H, m),4.55 (1H, m), 6.60 (1H, dd, J=2.4, 6.0 Hz), 6.92 (2H, m), 7.04 (2H, m),7.26 (1H, m), 7.50 (2H, m), 7.75 (1H, m), 8.03 (1H, d, J=6.0 Hz), 8.21(11H, m), 8.96 (1H, brs), 9.19 (1H, brs).

ESI-MS (m/z): 538 [M+H]⁺, 560 [M+Na]⁺.

Example 88N-(3-Fluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-3-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogenatmosphere, and triethylamine (0.181 ml) and phenyl chloroformate (0.163ml) were added while stirring and cooling in an ice water bath, followedby stirring at the same temperature for 15 min. The reaction mixture waspartitioned between ethyl acetate (30 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with brine (30 ml), and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. To the residuewas added N,N-dimethylformamide (1.5 ml), and (S)-3-pyrrolidinol (123mg) was added, followed by stirring at room temperature for 3 hr. Thereaction mixture was partitioned after addition of ethyl acetate (30 ml)and a saturated aqueous solution of sodium hydrogencarbonate (20 ml).The separated organic layer was washed with brine (30 ml), and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=1:5, ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure, and to the residue (158 mg)were added tert-butyl methyl ether (2 ml) and heptane (4 ml) to suspenda solid. The solid was collected by filtration and dried under aerationto provide the titled compound as white powder (146.1 mg, 76.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.30-2.00 (7H, m), 3.40-3.80 (4H, m),4.50 (1H, m), 6.67 (1H, dd, J=2.4, 6.0 Hz), 7.03 (2H, m), 7.12 (2H, m),7.20 (1H, m), 7.40-7.60 (2H, m), 7.60-7.80 (2H, m), 8.04 (1H, d, J=6.0Hz), 8.95 (1H, brs), 9.66 (1H, brs).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 89N-(2-Fluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(150 mg) was dissolved in tetrahydrofuran (1.5 ml) under a nitrogenatmosphere, triethylamine (0.181 ml) and phenyl chloroformate (0.163 ml)were added while stirring and cooling in an ice water bath, followed bystirring at the same temperature for 15 min. The reaction mixture waspartitioned between ethyl acetate (30 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (20 ml). The separated organiclayer was washed with brine (30 ml), and dried over anhydrous sodiumsulfate. The solvent was removed under reduced pressure. To the residuewas added N,N-dimethylformamide (1.5 ml), and (S)-3-pyrrolidinol (123mg) was added, followed by stirring at room temperature for 3 hr. Thereaction mixture was partitioned after addition of ethyl acetate (30 ml)and a saturated aqueous solution of sodium hydrogencarbonate (20 ml).The separated organic layer was washed with brine (30 ml), and driedover anhydrous sodium sulfate. The solvent was removed under reducedpressure, and the residue was purified by silica gel columnchromatography (eluent; heptane:ethyl acetate=1:5, ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure, and to the residue (169 mg)were added tert-butyl methyl ether (2 ml) and heptane (2 ml) to suspenda solid. The solid was collected by filtration and dried under aerationto provide the titled compound as white powder (151.9 mg, 79.8%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.30-2.00 (7H, m), 3.45-3.80 (4H, m),4.55 (1H, m), 6.60 (1H, dd, J=2.4, 6.0 Hz), 6.92 (2H, m), 7.04 (2H, m),7.26 (1H, m), 7.50 (2H, m), 7.75 (1H, m), 8.03 (1H, d, J=6.0 Hz), 8.21(1H, m), 8.96 (1H, brs), 9.19 (1H, brs).

ESI-MS (m/z): 560 [M+Na]⁺.

Example 90N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0630 ml) and phenyl chloroformate(0.0624 ml) were added dropwise at 0° C. in this order, followed bystirring for 30 min. The reaction mixture was stirred after addition ofethyl acetate (5 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withbrine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (1.0 ml). Triethylamine (0.315 ml) and azetidinehydrochloride (84.6 mg) were added at room temperature, followed bystirring for 16.5 hr. The reaction mixture was partitioned between ethylacetate (10 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was washed with brine, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. To the residue were added ethyl acetate (3 ml) andheptane (3 ml) to precipitate a solid. The solid was collected byfiltration. The resultant solid was washed with heptane:ethylacetate=1:1, dried under hot air at 60° C. for 4 hr to provide thetitled compound as white powder (94.0 mg, 79%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.56-1.66 (4H, m), 2.09-2.16 (2H, m),3.92-3.95 (4H, m), 6.63 (1H, dd, J=2.4, 5.6 Hz), 7.15-7.20 (2H, m), 7.51(1H, d, J=2.4 Hz), 7.54 (1H, dd, J=6.8, 11.2 Hz), 7.58-7.62 (2H, m),8.06-8.13 (1H, m), 8.13 (1H, d, J=5.6 Hz), 9.13 (1H, s), 9.81 (1H, d,J=4.4 Hz), 11.0 (1H, m).

ESI-MS (m/z): 526 [M+H]⁺.

Example 91N-[2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}1-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0630 ml) and phenyl chloroformate(0.0624 ml) were added dropwise at 0° C. in this order, followed bystirring for 30 min. The reaction mixture was stirred after addition ofethyl acetate (5 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withbrine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (1.0 ml). 3-Hydroxyazetidine hydrochloride (99.0mg) and triethylamine (0.315 ml) were added at room temperature,followed by stirring for 22 hr and 5 min. The reaction mixture waspartitioned between ethyl acetate (10 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (5 ml). The organic layer waswashed with brine, and dried over anhydrous sodium sulfate. The solventwas concentrated under reduced pressure. To the resultant residue wereadded ethyl acetate (1 ml) and heptane (1 ml) to precipitate a solid.The solid was collected by filtration. The resultant solid was purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate, then ethyl acetate:methanol=10:1), and fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white powder (71.1 mg, 58%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.55-1.68 (4H, m), 3.68 (2H, dd,J=4.4, 8.4 Hz), 4.10-4.14 (2H, m), 4.34-4.40 (1H, m), 5.60 (1H, d, J=6.4Hz), 6.64 (1H, dd, J=2.4, 5.6 Hz), 7.15-7.20 (2H, m), 7.50 (1H, d, J=2.4Hz), 7.52-7.62 (3H, m), 8.05-8.14 (1H, m), 8.13 (1H, d, J=5.6 Hz), 9.20(1H, s), 9.81 (1H, m), 10.99 (1H, m).

ESI-MS (neg.) (m/z): 540 [M−H]⁻.

Example 92N-(2,5-Difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(104.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0653 ml) and phenyl chloroformate(0.0646 ml) were added dropwise at 0° C. in this order, followed bystirring for 30 min. The reaction mixture was stirred after addition ofethyl acetate (5 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withbrine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (1.0 ml). 1-Methyl-4-(piperidin-4-yl)piperazine(172.0 mg) was added at room temperature, followed by stirring at 20 hrand 40 min. The reaction mixture was partitioned between ethyl acetate(10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5ml). The organic layer was washed with brine, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Tothe resultant residue were added ethyl acetate (5 ml) and heptane (5 ml)to precipitate a solid. The solid was collected by filtration. Theresultant solid was washed with heptane:ethyl acetate=1:1, and driedunder aeration to provide the titled compound as white powder (89.2 mg,59%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.12-1.32 (2H, m), 1.55-1.67 (4H, m),1.67-1.74 (2H, m), 2.12 (3H, s), 2.20-2.65 (7H, m), 2.65-2.80 (4H, m),4.05-4.15 (2H, m), 6.63 (1H, dd, J=2.4, 5.6 Hz), 7.18 (2H, m), 7.39 (1H,d, J=2.4 Hz), 7.52-7.62 (3H, m), 8.05-8.15 (1H, m), 8.13 (1H, d, J=5.6Hz), 9.24 (1H, s), 9.80 (1H, m), 10.99 (1H, m).

ESI-MS (m/z): 652 [M+H]⁺.

Example 93N-[2,5-Difluoro-4-({2-[({3-[(dimethylamino)methyl]azetidin-1-yl]carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(93.9 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0592 ml) and phenyl chloroformate(0.0586 ml) were added dropwise at 0° C. in this order, followed bystirring for 25 min. The reaction mixture was stirred after addition ofethyl acetate (5 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withbrine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (1.0 ml). 3-(Dimethylaminomethyl)azetidineditrifluoroacetate (363.0 mg) and triethylamine (0.591 ml) were added atroom temperature, followed by stirring for 19 hr and 45 min. Thereaction mixture was partitioned between ethyl acetate (10 ml) and asaturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was washed with water (10 ml) twice and brine in thisorder, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate, then ethyl acetate:methanol=10:1), and fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white powder (92.3 mg, 73%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.55-1.68 (4H, m), 2.10 (6H, s), 2.40(2H, d, J=7.2 Hz), 2.62-2.73 (1H, m), 3.54-3.62 (2H, m), 3.96-4.05 (2H,m), 6.64 (1H, dd, J=2.4, 5.6 Hz), 7.15-7.20 (2H, m), 7.50 (1H, d, J=2.4Hz), 7.50-7.61 (3H, m), 8.05-8.13 (1H, m), 8.13 (1H, d, J=5.6 Hz), 9.16(1H, s), 9.82 (1H, m), 10.99 (1H, m).

ESI-MS (m/z): 583 [M+H]⁺.

Example 94N-(2,5-Difluoro-4-{[2-({methyl(1-methyl]piperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(94.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, and triethylamine (0.0593 ml) and phenyl chloroformate(0.0587 ml) were added dropwise at 0° C. in this order, followed bystirring for 25 min. The reaction mixture was stirred after addition ofethyl acetate (5 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withbrine, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The residue was dissolved inN,N-dimethylformamide (1.0 ml). 1-Methyl-4-(methylamino)piperidine(0.123 ml) was added at room temperature, followed by stirring for 18 hrand 35 min. The reaction mixture was partitioned between ethyl acetate(10 ml) and a saturated aqueous solution of sodium hydrogencarbonate (5ml). The organic layer was washed with water (10 ml) twice and brine inthis order, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate, then ethyl acetate:methanol=10:1), and fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white powder (96.8 mg, 75%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.61-1.83 (8H, m), 2.03-2.10 (2H, m),2.28 (3H, s), 2.88 (3H, s), 2.90-2.94 (2H, m), 4.10-4.20 (1H, m), 6.55(1H, dd, J=2.4, 5.6 Hz), 6.98-7.08 (3H, m), 7.15 (1H, s), 7.46-7.50 (2H,m), 7.67 (1H, d, J=2.4 Hz), 8.08 (1H, d, J=5.6 Hz), 8.29 (1H, dd, J=7.2,12.0 Hz), 8.57 (1H, s), 9.59 (1H, s).

ESI-MS (m/z): 597 [M+H]⁺.

Example 95N-{4-[(2-{[3-(Azetidin-1-ylmethyl)azetidin-1-ylcarbonyl]amino}pyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(94.7 mg) was dissolved in tetrahydrofuran (2.5 ml) under a nitrogenatmosphere, and triethylamine (0.100 ml) and phenyl chloroformate (0.070ml) were added dropwise at room temperature in this order, followed bystirring for 15 min. The reaction mixture was stirred after addition ofethyl acetate and water. The organic layer was separated, washed with a1N aqueous solution of sodium hydroxide, water and brine, dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (2.5 ml).Triethylamine (0.315 ml) and 3-(azetidin-1-ylmethyl)azetidinedihydrochloride (180 mg) were added at room temperature, followed bystirring overnight. The reaction mixture was partitioned between ethylacetate and water. The organic layer was washed with a 1N aqueoussolution of sodium hydroxide, water and brine in this order, and driedover anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5). Fractions containing the target compoundwere concentrated under reduced pressure. To the resultant residue wasadded tert-butyl methyl ether:heptane=1:2 to precipitate a solid. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (50.0 mg, 39%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.55-1.80 (4H, m), 2.10 (2H, m),2.55-2.70 (3H, m), 3.10-3.30 (4H, m), 3.71 (2H, m), 4.10 (2H, m), 6.57(1H, dd, J=2.4, 5.6 Hz), 6.78 (1H, brs), 6.95-7.10 (3H, m), 7.40-7.55(2H, m), 7.62 (1H, d, J=2.4 Hz), 8.05 (1H, d, J=5.6 Hz), 8.29 (1H, m),8.66 (1H, brs), 9.51 (1H, brs).

ESI-MS (m/z): 595 [M+H]⁺.

Example 96N-(2,5-Difluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(108.2 mg) was dissolved in tetrahydrofuran (2.5 ml) under a nitrogenatmosphere, and triethylamine (0.100 ml) and phenyl chloroformate (0.080ml) were added dropwise at room temperature in this order, followed bystirring for 15 min. The reaction mixture was stirred after addition ofethyl acetate and water. The organic layer was separated, washed with a1N aqueous solution of sodium hydroxide, water and brine, dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (2.5 ml).Triethylamine (0.256 ml) and 3-(hydroxymethyl)azetidine hydrochloride(182 mg) were added at room temperature, followed by stirring overnight.The reaction mixture was partitioned between ethyl acetate and water.The organic layer was washed with a 1N aqueous solution of sodiumhydroxide, water and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography(eluent; ethyl acetate, then ethyl acetate:methanol=95:5). Fractionscontaining the target compound were concentrated under reduced pressure.To the resultant residue was added tert-butyl methyl ether:heptane=1:2to precipitate a solid. The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (38.1 mg,28%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.50-1.80 (4H, m), 2.83 (1H, m), 3.80(2H, d, J=6.0 Hz), 3.93 (2H, m), 4.18 (2H, m), 6.57 (1H, dd, J=2.4, 5.6Hz), 6.95-7.10 (4H, m), 7.40-7.55 (2H, m), 7.78 (1H, d, J=2.4 Hz), 7.99(1H, d, J=5.6 Hz), 8.33 (1H, m), 8.48 (1H, brs), 9.79 (1H, brs).

ESI-MS (m/z): 578 [M+Na]⁺.

Example 97N-{2,5-Difluoro-4-[(4-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyrimidin-6-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogenatmosphere, triethylamine (0.080 ml) and phenyl chloroformate (0.070 ml)were added dropwise at room temperature, followed by stirring for 10min. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was separated, washed with a 1N aqueoussolution of sodium hydroxide and brine, dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (2.5 ml). To the solutionwere added 3-hydroxyazetidine hydrochloride (150 mg) and triethylamine(0.250 ml) at room temperature, followed by stirring for 63 hr. Thereaction mixture was partitioned between ethyl acetate and water. Theorganic layer was separated, washed with a 1N aqueous solution of sodiumhydroxide and brine, dried over anhydrous sodium sulfate. The solventwas concentrated under reduced pressure. The resultant residue waspurified by silica gel column chromatography (Fuji Silysia NH, eluent;ethyl acetate, then ethyl acetate:methanol=95:5), and fractionscontaining the target compound were concentrated under reduced pressure.To the resultant residue was added diethyl ether:heptane=1:2 toprecipitate a solid. The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (57.3 mg,47%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.27 (1H, m), 4.00(2H, m), 4.37 (2H, m), 4.75 (1H, m), 6.90-7.10 (4H, m), 7.40-7.55 (2H,m), 7.66 (1H, s), 8.28 (1H, dd, J=7.2, 12.0 Hz), 8.34 (1H, s), 8.66 (1H,brs), 9.50 (1H, brs).

ESI-MS (m/z): 565 [M+Na]⁺.

Example 98N-[4-({4-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyrimidin-6-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(99.0 mg) was dissolved in tetrahydrofuran (10 ml) under a nitrogenatmosphere, triethylamine (0.0622 ml) and phenyl chloroformate (0.0615ml) were added dropwise at 0° C., followed by stirring for 40 min., thenstirred for 20 min. at room temperature. Triethylamine (0.0622 ml) andphenyl chloroformate (0.0615 ml) were added again at room temperature,followed by stirring for 1 hr. The reaction mixture was stirred afteraddition of ethyl acetate (5 ml) and a saturated aqueous solution ofsodium hydrogencarbonate (5 ml). The organic layer was separated, washedwith brine, dried over anhydrous sodium sulfate and filtrated. Thesolvent was concentrated under reduced pressure. The residue wasdissolved in N,N-dimethylformamide (2.0 ml). This was added to3-(dimethylaminomethyl)azetidine ditrifluoroacetate (227 mg) at roomtemperature under a nitrogen atmosphere, then triethylamine (0.623 ml)was added thereto, followed by stirring for 13 hr and 30 min. Thereaction mixture was partitioned between ethyl acetate (10 ml) and asaturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with twice in water (10 ml) andbrine in this order, and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure. To the resultantresidue was added ethyl acetate:heptane=1:4 to precipitate the solid.The solid was collected by filtration. This was dissolved in ethanol (4ml), and a 1N aqueous solution of sodium hydroxide (0.233 ml) was addedat room temperature, followed by stirring for 1.5 hr. After the reactionwas quenched by addition of 1N hydrochloric acid (0.223 ml) at roomtemperature, ethyl acetate (30 ml) and water (20 ml) were added to thereaction mixture. The separated organic layer was washed with brine,dried over anhydrous sodium sulfate and filtrated. The solvent wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate, then ethyl acetate:methanol=10:1), and fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white powder (60.8 mg, 47%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.66-1.71 (4H, m), 2.24 (6H, s), 2.55(2H, d, J=7.6 Hz), 2.80-2.90 (1H, m), 3.77 (2H, dd, J=5.6, 8.4 Hz), 4.19(2H, t, J=8.4 Hz), 6.93 (1H, brs), 7.01-7.10 (3H, m), 7.45-7.50 (2H, m),7.66 (1H, s), 8.27 (1H, dd, J=7.2, 11.6 Hz), 8.33-8.35 (1H, m), 8.68(1H, brs), 9.45-9.49 (1H, m).

ESI-MS (m/z): 584 [M+H]⁺.

Example 99N-(2,5-Difluoro-4-{[4-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (7.5 ml) under a nitrogenatmosphere, triethylamine (0.180 ml) and phenyl chloroformate (0.150 ml)were added dropwise at room temperature, followed by stirring for 50min. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was separated, washed with a 1N aqueoussolution of sodium hydroxide and brine, dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (2.5 ml). To the solutionwere added triethylamine (0.400 ml) and 3-(hydroxymethyl)azetidinehydrochloride (280 mg) at room temperature, followed by stirringovernight. The reaction mixture was partitioned between ethyl acetateand water. The organic layer was separated, washed with a 1N aqueoussolution of sodium hydroxide and brine, dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography(eluent; ethyl acetate, then ethyl acetate:methanol=95:5), and fractionscontaining the target compound were concentrated under reduced pressure.To the resultant residue was added tert-butyl methyl ether:heptane=1:2to precipitate a solid. The solid was collected by filtration and driedunder aeration to provide the titled compound as white powder (15.6 mg,12%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.83 (1H, m), 3.82(2H, d, J=6.0 Hz), 3.93 (2H, m), 4.16 (2H, m), 6.90-7.15 (4H, m),7.40-7.55 (2H, m), 7.66 (1H, s), 8.22 (1H, dd, J=7.2, 12.0 Hz), 8.33(1H, s), 8.73 (1H, brs), 9.60 (1H, brs).

ESI-MS (m/z): 579 [M+Na]⁺.

Example 100N-(2,5-Difluoro-4-{[4-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (7.5 ml) under a nitrogenatmosphere, triethylamine (0.180 ml) and phenyl chloroformate (0.150 ml)were added dropwise at room temperature, followed by stirring for 50min. The reaction mixture was partitioned between ethyl acetate andwater. The organic layer was separated, washed with a 1N aqueoussolution of sodium hydroxide and brine, dried over anhydrous sodiumsulfate. The solvent was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (2.5 ml). To the solutionwas added 1-methyl-(4-methylamino)piperidine (0.330 ml) at roomtemperature, followed by stirring overnight. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with a 1N aqueous solution of sodium hydroxide andbrine, dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5), and fractions containing the targetcompound were concentrated under reduced pressure. To the resultantresidue was added tert-butyl methyl ether:heptane=1:2 to precipitate asolid. The solid was collected by filtration and dried under aeration toprovide the titled compound as white powder (19.5 mg, 14%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (8H, m), 2.20-2.60 (2H, m),2.96 (3H, s), 3.00-3.30 (2H, m), 3.22 (3H, s), 4.33 (1H, m), 6.90-7.15(4H, m), 7.40-7.55 (2H, m), 7.66 (1H, s), 8.27 (1H, dd, J=7.2, 12.0 Hz),8.35 (1H, s), 8.62 (1H, brs), 9.53 (1H, brs).

ESI-MS (m/z): 620 [M+Na]⁺.

Example 101N-(2,5-Difluoro-4-{[4-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogenatmosphere, N,N-diisopropylethylamine (0.100 ml) and phenylchloroformate (0.070 ml) were added dropwise at room temperature,followed by stirring for 15 min. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith a saturated aqueous solution of sodium hydrogencarbonate and brine,dried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(2.5 ml). To the solution was added1-methyl-4-(piperidin-4-yl)piperazine (250 mg) at room temperature,followed by stirring for 25 hr. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith a 1N aqueous solution of sodium hydroxide and brine, dried overanhydrous sodium sulfate. The solvent was concentrated under reducedpressure. The resultant residue was purified by silica gel columnchromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethylacetate:methanol=95:5), and fractions containing the target compoundwere concentrated under reduced pressure. To the resultant residue wasadded diethyl ether:heptane=1:2 to precipitate a solid. The solid wascollected by filtration and dried under aeration to provide the titledcompound as white powder (93.4 mg, 63%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.45-1.60 (2H, m), 1.66-1.76 (4H, m),1.90-1.98 (2H, m), 2.34 (3H, s), 2.42-2.72 (9H, m), 2.95 (2H, m), 4.12(2H, m), 7.00-7.10 (3H, m), 7.38 (1H, brs), 7.44-7.55 (2H, m), 7.62 (1H,s), 8.27 (1H, dd, J=6.8, 12.0 Hz), 8.33 (1H, s), 8.67 (1H, brs), 9.47(1H, brs).

ESI-MS (m/z): 653 [M+H]⁺.

Example 102N-(4-{[4-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(4-Aminopyrimidin-6-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100 mg) was dissolved in tetrahydrofuran (5 ml) under a nitrogenatmosphere, N,N-diisopropylethylamine (0.100 ml) and phenylchloroformate (0.070 ml) were added dropwise at room temperature,followed by stirring for 15 min. The reaction mixture was partitionedbetween ethyl acetate and water. The organic layer was separated, washedwith a saturated aqueous solution of sodium hydrogencarbonate and brine,dried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The residue was dissolved in N,N-dimethylformamide(2.5 ml). To the solution were added 4-dimethylaminopiperidinedihydrochloride (250 mg) and triethylamine (0.400 ml) at roomtemperature, followed by stirring for 25 hr. The reaction mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with a 1N aqueous solution of sodium hydroxide andbrine, dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=95:5), and fractions containing the targetcompound were concentrated under reduced pressure. To the resultantresidue was added diethyl ether:heptane=1:2 to precipitate a solid. Thesolid was collected by filtration and dried under aeration to providethe titled compound as white powder (100.3 mg, 74%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.46-1.56 (2H, m), 1.66-1.76 (4H, m),1.86-1.96 (2H, m), 2.31 (6H, s), 2.38 (1H, m), 2.97 (2H, m), 4.06-4.16(2H, m), 7.00-7.10 (3H, m), 7.39 (1H, brs), 7.44-7.54 (2H, m), 7.63 (1H,s), 8.27 (1H, dd, J=7.2, 12.0 Hz), 8.34 (1H, s), 8.68 (1H, brs), 9.47(1H, brs).

ESI-MS (m/z): 598 [M+H]⁺.

Example 103N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, triethylamine (0.0631 ml) and phenyl chloroformate (0.0624ml) were added dropwise at 0° C., followed by stirring for 20 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) anda saturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate and filtrated. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (3.0 ml).4-dimethylaminopiperidine dihydrochloride (227 mg) and triethylamine(0.631 ml) were added at room temperature under a nitrogen atmosphere,followed by stirring for 18 hr and 30 min. The reaction mixture waspartitioned between ethyl acetate (10 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (5 ml). The organic layer wasseparated, washed with water (10 ml, twice) and brine in this order, anddried over anhydrous sodium sulfate. The solvent was concentrated underreduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=10:1), and fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as white powder (107.5 mg, 78%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.20-1.30 (4H, m), 1.55-1.74 (6H, m),2.15 (6H, s), 2.71-2.80 (1H, s), 4.06-4.12 (2H, m), 6.63 (1H, dd, J=2.4,5.6 Hz), 7.15-7.2 (2H, m), 7.39-7.41 (1H, m), 7.51-7.63 (3H, m),8.05-8.1 (1H, m), 8.13 (1H, d, J=5.6 Hz), 9.23-9.26 (1H, m), 9.78-9.85(1H, m), 10.98-11.01 (1H, m).

ESI-MS (m/z): 597 [M+H]⁺.

Example 104N-{2,5-Difluoro-4-[(2-{[(4-methylpiperazin-1-yl)carbonyl]amino}pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, triethylamine (0.0631 ml) and phenyl chloroformate (0.0624ml) were added dropwise at 0° C., followed by stirring for 20 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) anda saturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate and filtrated. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml).1-Methylpiperazine (0.100 ml) was added at room temperature under anitrogen atmosphere, followed by stirring for 18 hr and 15 min. Thereaction mixture was partitioned between ethyl acetate (10 ml) and asaturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with water (10 ml, twice) and brinein this order, and dried over anhydrous sodium sulfate. The solvent wasconcentrated under reduced pressure. The resultant residue was purifiedby silica gel column chromatography (Fuji Silysia NH, eluent; ethylacetate, then ethyl acetate:methanol=10:1), and fractions containing thetarget compound were concentrated under reduced pressure to provide thetitled compound as white powder (113.1 mg, 87%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.56-1.67 (4H, m), 2.17 (3H, m),2.24-2.28 (4H, m), 3.38-3.43 (4H, m), 6.62-6.65 (1H, m), 7.15-7.20 (2H,m), 7.39-7.40 (1H, m), 7.52-7.63 (3H, m), 8.06-8.16 (1H, m), 8.14 (1H,d, J=6.4 Hz), 9.27-9.28 (1H, m), 9.79-9.81 (1H, m), 10.98-11.00 (1H, m).

ESI-MS (m/z): 591 [M+Na]⁺.

Example 105N-{2,5-Difluoro-4-[(2-[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(129.0 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogenatmosphere, triethylamine (0.0812 ml) and phenyl chloroformate (0.0803ml) were added dropwise at 0° C., followed by stirring for 25 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) anda saturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate and filtrated. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml). Asolution of 4-hydroxypiperidine (118 mg) in N,N-dimethylformamide (2 ml)was added at room temperature under a nitrogen atmosphere, followed bystirring for 17 hr and 15 min. The reaction mixture was partitionedbetween ethyl acetate (10 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withtwice in water (10 ml) and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1),and fractions containing the target compound were concentrated underreduced pressure to provide the titled compound as white powder (158.4mg, 92%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.22-1.33 (2H, m), 1.55-1.73 (6H, m),3.00-3.07 (2H, m), 3.59-3.67 (1H, m), 3.74-3.82 (2H, m), 4.67 (1H, d,J=4.4 Hz), 6.62 (1H, dd, J=2.4, 5.6 Hz), 7.15-7.21 (2H, m), 7.40 (1H, d,J=2.4 Hz), 7.54 (1H, dd, J=7.2, 10.4 Hz), 7.57-7.63 (2H, m), 8.05-8.15(1H, m), 8.13 (1H, d, J=5.6 Hz), 9.23 (1H, brs), 9.80-9.83 (1H, m),10.97-11.01 (1H, m).

ESI-MS (m/z): 592 [M+Na]⁺.

Example 106N-[2,3-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,3-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(84.0 mg) was dissolved in tetrahydrofuran (1 ml) under a nitrogenatmosphere, triethylamine (0.0530 ml) and phenyl chloroformate (0.0524ml) were added dropwise at 0° C., followed by stirring for 20 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) anda saturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate and filtrated. The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (2.0 ml).3-hydroxyazetidine hydrochloride (83.3 mg) and triethylamine (0.265 ml)were added at room temperature under a nitrogen atmosphere, followed bystirring for 12 hr and 25 min. The reaction mixture was partitionedbetween ethyl acetate (10 ml) and a saturated aqueous solution of sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withtwice in water (10 ml) and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1),and fractions containing the target compound were concentrated underreduced pressure to provide the titled compound as white powder (80.3mg, 78%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.53-1.62 (4H, m), 3.66-3.72 (2H, m),4.10-4.15 (2H, m), 4.34-4.40 (1H, m), 5.60 (1H, d, J=6.0 Hz), 6.66 (1H,dd, J=2.4, 5.6 Hz), 7.15-7.25 (3H, m), 7.52 (1H, d, J=2.4 Hz), 7.60-7.65(2H, m), 7.70-7.78 (1H, m), 8.14 (1H, d, J=5.6 Hz), 9.22 (1H, brs),9.95-9.99 (1H, m), 10.68-10.71 (1H, m).

ESI-MS (m/z): 564 [M+Na]⁺.

Example 107N-[4-({2-[({3-[(Dimethylamino)methyl]azetidine-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2,3-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,3-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(79.2 mg) was dissolved in tetrahydrofuran (2 ml) under a nitrogenatmosphere, triethylamine (0.0500 ml) and phenyl chloroformate (0.0494ml) were added dropwise at 0° C., followed by stirring for 20 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) anda saturated aqueous solution of sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with brine, dried over anhydroussodium sulfate. After filtering the desiccant off, the filtrate wasmoved to a flask with 3-(dimethylaminomethyl)azetidineditrifluoroacetate (434 mg). The solvent was concentrated under reducedpressure. The residue was dissolved in N,N-dimethylformamide (5.0 ml).Triethylamine (0.750 ml) was added at room temperature under a nitrogenatmosphere, followed by stirring for 13 hr. The reaction mixture waspartitioned between ethyl acetate (10 ml) and a saturated aqueoussolution of sodium hydrogencarbonate (5 ml). The organic layer wasseparated, washed with twice in water (10 ml) and brine in this order,and dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate, thenethyl acetate:methanol=10:1), and fractions containing the targetcompound were concentrated under reduced pressure to provide the titledcompound as white powder (83.0 mg, 80%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.53-1.62 (4H, m), 2.10 (6H, s), 2.39(2H, d, J=7.6 Hz), 2.65-2.68 (1H, m), 3.53-3.60 (2H, m), 3.95-4.04 (2H,m), 6.95-6.98 (1H, m), 7.14-7.25 (4H, m), 7.52 (1H, d, J=2.4 Hz),7.60-7.66 (2H, m), 7.70-7.78 (1H, m), 8.14 (1H, d, J=5.6 Hz), 9.17 (1H,brs), 9.95-9.98 (1H, m), 10.66-10.71 (1H, m).

ESI-MS (m/z): 583 [M+H]⁺.

Example 108N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]oxy}-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogenatmosphere, triethylamine (0.0631 ml) and phenyl chloroformate (0.0624ml) were added dropwise at 0° C., followed by stirring for 1 hr. Thentriethylamine (0.0631 ml) and phenyl chloroformate (0.0624 ml) wereadded dropwise at 0° C., followed by stirring for 20 min. The reactionmixture was stirred after addition of ethyl acetate (5 ml) and saturatedsodium hydrogencarbonate (5 ml). The organic layer was separated, washedwith brine, dried over anhydrous sodium sulfate and filtrated. Thesolvent was concentrated under reduced pressure. The residue wasdissolved in N,N-dimethylformamide (2.0 ml). 4-(Azetidin-1-yl)piperidinedihydrochloride (227.0 mg) and triethylamine (0.631 ml) were added atroom temperature under a nitrogen atmosphere, followed by stirring for16 hr and 30 min. The reaction mixture was partitioned between ethylacetate (10 ml) and saturated sodium hydrogencarbonate (5 ml). Theorganic layer was separated, washed with twice in water (10 ml) andbrine in this order, and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; ethyl acetate, then ethyl acetate:methanol=10:1), and fractionscontaining the target compound were concentrated under reduced pressure.To the resultant residue was added heptane:ethyl acetate=10:1 to suspenda solid. The solid was collected by filtration. This solid was purifiedby preparative TLC (Fuji Silysia NH TLC plate, eluent; ethyl acetate),and following short column chromatography (Fuji Silysia NH, eluent;ethyl acetate). Fractions containing the target compound wereconcentrated under reduced pressure. To the resultant residue was addedheptane:ethyl acetate=10:1 to suspend a solid. The solid was collectedby filtration to provide the titled compound as white powder (24.0 mg,17%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.20-1.33 (4H, m), 1.67-1.75 (4H, m),2.01-2.09 (2H, m), 2.13-2.23 (1H, m), 2.99-3.08 (2H, m), 3.15-3.20 (4H,m), 3.85-3.92 (2H, m), 6.55 (1H, dd, J=2.4, 5.6 Hz), 6.98-7.07 (3H, m),7.46-7.50 (2H, m), 7.60 (1H, d, J=2.4 Hz), 8.06 (1H, d, J=5.6 Hz), 8.28(1H, dd, J=7.2, 11.6 Hz), 8.66 (1H, brs), 9.49 (1H, brs).

ESI-MS (m/z): 609 [M+H]⁺.

Example 109N-(2,5-Difluoro-4-{[2-({[3-(2-dimethylaminoacetoxy)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(38.9 mg) was dissolved in N,N-dimethylformamide (1.0 ml) under anitrogen atmosphere, and N,N-dimethylglycine hydrochloride (20 mg),triethylamine (0.050 ml) and BOP reagent (63.5 mg) were added at roomtemperature, followed by stirring overnight. N,N-Dimethylglycinehydrochloride (20 mg), triethylamine (0.050 ml) and BOP reagent (63.5mg) were added again at room temperature, and the reaction mixture wasstirred for 5 hr. The reaction mixture was partitioned between ethylacetate and water. The organic layer was separated, washed with asaturated aqueous solution of sodium hydrogencarbonate (twice) andbrine, dried over anhydrous sodium sulfate. The solvent was concentratedunder reduced pressure. The resultant residue was purified by silica gelcolumn chromatography (Fuji Silysia NH, eluent; ethyl acetate), andfractions containing the target compound were concentrated under reducedpressure. To the resultant residue was added tert-butyl methyl ether (1ml)-heptane (2 ml) to precipitate a solid. The solid was collected byfiltration and dried under aeration to provide the titled compound aswhite powder (21.1 mg, 47%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (4H, m), 2.38 (6H, s), 3.24(2H, s), 4.05 (2H, m), 4.39 (2H, m), 5.28 (1H, m), 6.59 (1H, dd, J=2.4,5.6 Hz), 6.90-7.15 (4H, m), 7.40-7.55 (2H, m), 7.62 (1H, d, J=2.4 Hz),8.05 (1H, d, J=5.6 Hz), 8.29 (1H, dd, J=7.2, 12.0 Hz), 8.56 (1H, brs),9.65 (1H, brs).

ESI-MS (m/z): 649 [M+Na]⁺.

Example 110N-(2,5-Difluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogenatmosphere, triethylamine (0.0630 ml) and phenyl chloroformate (0.0624ml) were added dropwise at 0° C., followed by stirring for 30 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) andsaturated sodium hydrogencarbonate (5 ml). The organic layer wasseparated, washed with brine, dried over anhydrous sodium sulfate andfiltered it. The solvent was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (2.0 ml).(S)-3-Hydroxypyrrolidine was added at room temperature under a nitrogenatmosphere, followed by stirring 22 hr. The reaction mixture waspartitioned between ethyl acetate (10 ml) and saturated sodiumhydrogencarbonate (5 ml). The organic layer was separated, washed withtwice in water (10 ml) and brine in this order, and dried over anhydroussodium sulfate. The solvent was concentrated under reduced pressure. Theresultant residue was purified by silica gel column chromatography (FujiSilysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=10:1),and fractions containing the target compound were concentrated underreduced pressure. To the resultant residue was added heptane:ethylacetate=10:1 to suspend a solid. The solid was collected by filtrationto provide the titled compound as white powder (63.7 mg, 51%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.60-1.80 (5H, m), 2.00-2.14 (2H, m),3.47-3.67 (4H, m), 4.51-4.60 (1H, m), 6.58 (1H, dd, J=2.4, 5.6 Hz),6.98-7.12 (3H, m), 7.45-7.52 (2H, m), 7.67 (1H, d, J=2.4 Hz), 8.07 (1H,d, J=5.6 Hz), 8.25-8.30 (1H, m), 8.68 (1H, brs), 9.50-9.57 (1H, m).

ESI-MS (neg.)(m/z): 554 [M−H]⁻.

Example 111N-(2,5-Difluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide

N-{4-[(2-Aminopyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(100.0 mg) was dissolved in tetrahydrofuran (2.0 ml) under a nitrogenatmosphere, triethylamine (0.0630 ml) and phenyl chloroformate (0.0624ml) were added dropwise at 0° C., followed by stirring for 30 min. Thereaction mixture was stirred after addition of ethyl acetate (5 ml) andsaturated sodium hydrogencarbonate (5 ml). The organic layer wasseparated, washed with brine, dried over anhydrous sodium sulfate andfiltered it. The solvent was concentrated under reduced pressure. Theresidue was dissolved in N,N-dimethylformamide (2.0 ml).(R)-(−)-3-Pyrrolidinol hydrochloride (112.0 mg) and triethylamine (0.315ml) were added at room temperature under a nitrogen atmosphere, followedby stirring 22 hr and 15 min. The reaction mixture was partitionedbetween ethyl acetate (10 ml) and saturated sodium hydrogencarbonate (5ml). The organic layer was separated, washed with twice in water (10 ml)and brine in this order, and dried over anhydrous sodium sulfate. Thesolvent was concentrated under reduced pressure. The resultant residuewas purified by silica gel column chromatography (Fuji Silysia NH,eluent; ethyl acetate, then ethyl acetate:methanol=10:1), and fractionscontaining the target compound were concentrated under reduced pressure.To the resultant residue was added heptane:ethyl acetate=10:1 to suspenda solid. The solid was collected by filtration to provide the titledcompound as white powder (76.4 mg, 61%).

¹H-NMR Spectrum (CDCl₃) δ (ppm): 1.65-1.70 (5H, m), 2.00-2.17 (2H, m),3.46-3.68 (4H, m), 4.52-4.59 (1H, m), 6.57 (1H, dd, J=2.4, 5.6 Hz),6.97-7.11 (3H, m), 7.46-7.50 (2H, m), 7.67 (1H, d, J=2.4 Hz), 8.07 (1H,d, J=5.6 Hz), 8.27 (1H, dd, J=7.2, 11.6 Hz), 8.68 (1H, brs), 9.54 (1H,brs).

ESI-MS (neg.)(m/z): 554[M−H]⁻.

Example 112N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidehydrochloride

N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(25.4 mg) was suspended in acetone (0.254 ml). To this was added a 5Mhydrochloric acid (0.010 ml) at room temperature, followed by stirringfor 3 hr. After adding of acetone (0.127 ml), insoluble matter wascollected by filtration and washed with acetone (0.127 ml, twice). Thiswas dried under aeration at room temperature, then hot air-dried at 60°C. to provide the titled compound as white powder (26.5 mg, 97%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.52-1.70 (4H, m), 2.22 (2H, m),3.96-4.12 (4H, m), 7.00-7.10 (2H, m), 7.14-7.24 (3H, m), 7.42 (1H, m),7.55-7.65 (2H, m), 8.07 (1H, m), 8.25 (1H, d, J=7.2 Hz), 9.90 (1H, brs),10.38 (1H, br), 10.80 (1H, brs).

Example 113N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidehydrochloride

N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(31.7 mg) was suspended in acetone (0.317 ml). To this was added a 5Mhydrochloric acid (0.010 ml) and water (0.0059 ml) at room temperature,followed by stirring for 5 hr. After adding of acetone (0.317 ml),insoluble matter was collected by filtration and washed with acetone(0.159 ml, twice). This was dried under aeration at room temperature,then hot air-dried at 60° C. to provide the titled compound as whitepowder (32.1 mg, 96%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.47 (2H, m), 1.58 (2H, m), 1.64 (2H,m), 1.97 (2H, m), 2.71 (6H, s), 2.96 (2H, m), 3.50-4.40 (6H, m), 4.59(2H, m), 7.01 (1H, m), 7.10-7.25 (4H, m), 7.41 (1H, m), 7.55-7.65 (2H,m), 8.06 (1H, m), 8.27 (1H, d, J=6.8 Hz), 9.92 (1H, brs), 10.61 (1H,br), 10.80 (1H, brs), 12.30 (1H, br).

Example 114N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide1/2 sulfate

N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide(28.0 mg) was suspended in acetone (0.280 ml). To this was added a 2.5Msulfuric acid (0.010 ml) and water (0.004 ml) at room temperature,followed by stirring overnight. After adding of acetone (0.140 ml),insoluble matter was collected by filtration and washed with acetone(0.140 ml, twice). This was dried under aeration at room temperature,then hot air-dried at 60° C. to provide the titled compound as whitepowder (28.2 mg, 93%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.50-1.70 (4H, m), 1.70-1.80 (2H, m),1.85-2.00 (2H, m), 2.77 (3H, s), 2.81 (3H, s), 3.00-3.15 (2H, m),3.40-3.50 (2H, m), 4.27 (1H, m), 6.81 (1H, m), 7.00-7.20 (2H, m),7.22-7.40 (4H, m), 7.50-7.65 (2H, m), 7.99 (1H, m), 8.20 (1H, d, J=6.0Hz), 9.20 (1H, br), 9.90 (1H, brs), 10.66 (1H, brs).

Example 115N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide1/2 sulfate

N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-3-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(25.4 mg) was suspended in acetone (0.254 ml). To this was added a 2.5Msulfuric acid (0.010 ml) at room temperature, followed by stirring for3.5 hr. After adding of acetone (0.127 ml), insoluble matter wascollected by filtration and washed with acetone (0.127 ml, twice). Thiswas dried under aeration at room temperature, then hot air-dried at 60°C. to provide the titled compound as white powder (23.5 mg, 85%).

¹H-NMR Spectrum (DMSO-d6) δ (ppm): 1.40-1.56 (4H, m), 2.23 (2H, m),3.96-4.14 (4H, m), 6.88 (1H, m), 7.05-7.20 (3H, m), 7.44 (1H, m), 7.54(1H, m), 7.60-7.70 (2H, m), 7.92 (1H, dd, J=2.4, 13.2 Hz), 8.27 (1H, d,J=6.8 Hz), 9.96 (1H, brs), 10.27 (1H, br), 10.46 (1H, brs).

Example 116N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideL-tartarate

N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide(63.4 mg) was suspended in ethanol (1.168 ml). To this was added a 1Msolution of L-(+)-tartaric acid in ethanol (0.100 ml), followed byheating at 50° C. Water (0.1268 ml) was added thereto to dissolvecompletely. The reaction mixture was stirred at 50° C. for 1 hr and 45min, then stirred overnight while allowing it to gradually cool down toroom temperature. Insoluble matter was collected by filtration andwashed with ethanol (0.200 ml). This was dried under aeration at roomtemperature to provide the titled compound as colorless crystals (66.7mg, 85.1%).

¹H-NMR Spectrum (DMSO-d₆) δ (ppm): 1.29 (2H, m), 1.68 (4H, m), 1.74 (2H,m), 2.35 (3H, s), 2.40-2.70 (9H, m), 2.77 (2H, m), 4.07 (2H, s), 4.12(2H, m), 6.61 (1H, dd, J=2.4, 6.0 Hz), 7.01 (1H, m), 7.17 (2H, m), 7.23(1H, m), 7.40 (1H, d, J=2.4 Hz), 7.59-7.63 (2H, m), 7.92 (1H, m), 8.14(1H, d, J=6.0 Hz), 9.24 (1H, s), 9.96 (1H, m), 10.56 (1H, s).

Pharmacological Test Examples

The biological activity and pharmaceutical effect (inhibitory activityfor hepatocyte growth factor receptor, anti-tumor activity, inhibitoryactivity for angiogenesis, and inhibitory activity for cancermetastasis) of the compound according to the present invention wereevaluated by methods described below.

Abbreviations and terms used in the following Pharmacological TestExamples are listed as follows:

Abbreviation List

-   HGFR (Hepatocyte growth factor receptor)-   DNA (Deoxyribonucleic acid)-   Human placenta-   PCR (Polymerase chain reaction)-   VEGFR2 (Vascular endothelial growth factor receptor 2)-   FGFR1 (Fibroblast growth factor receptor 1)-   PDGFRβ (Platelet derived growth factor receptor)-   EGFR (Epidermal growth factor receptor)-   FBS (Fetal bovine serum)-   PBS (Phosphate buffered saline)-   Tris (Tris(hydroxymethyl)aminomethane, Tris(buffer))-   PMSF (Phenylmethylsulfonyl fluoride)-   NP-40 (Nonidet P-40)-   EGTA (O,O-Bis(2-aminoethyleneglycol)-N,N,N′,N′-tetraacetic acid)-   SDS (Sodium dodecyl sulfate)-   BSA (Bovine serum albumin)-   Hepes (N-[2-hydroxyethyl]piperazine-N′-[2-ethanesulfonic acid],    Hepes(buffer))-   ATP (Adenosine 5′-triphosphate)-   EDTA (Ethylenediamine tetraacetic acid)-   HTRF (Homogenous Time-Resolved Fluorescence)-   HRP (Horseradish peroxidase)-   ELISA (Enzyme-linked immunosorbent assay)-   HGF (Hepatocyte growth factor)-   HBSS (Hank's Balanced Salt solution)-   MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide;    Thiazolyl blue)-   EGM-2 (Endothelial Cell Growth Medium-2)

Pharmacological Test Example 1 Inhibitory Activity Against ReceptorTyrosine Kinase Activity

1. Cloning of Receptor Tyrosine Kinases and Preparation of theRecombinant Baculovirus Solutions

The cytoplasmic domain of HGFR (Genbank Accession No. J02958) is a 1.3kb DNA fragment beginning with Lys974 and including a stop codon, anddescribed by Park et al. (Proc. Natl. Acad. Sci. U.S.A. 84(18),6379-6383, 1987). The DNA fragment was isolated from the human placentalcDNA library (purchased from Clontech) by PCR (TaKaRa Ex Taq™ Kit,purchased from TaKaRa) using two kinds of primers (SEQ ID NO:1,5′-CCGGCCGGATCCAAAAAGAGAAAGCAAATTAAA-3′ and SEQ ID NO:2,5′-TTAATTCTGCAGCTATGATGTCTCCCAGAAGGA-3′, purchased from Invitrogen).The DNA fragment was cloned into a baculovirus transplace vector(pFastBac™-HT (purchased from GIBCO BRL)) to produce a recombinantconstruct. The construct was transfected into insect cells (Spodopterafrugiperda 9(Sf9)) to produce a solution of HGFR transfected baculovirus(preparation of a recombinant baculovirus can be found in the standardtext (Bac-to-Bac Baculovirus Expression System (GIBCO BRL)). The cloningof the other receptor tyrosine kinases and preparation of therecombinant baculovirus solutions were prepared using a cytoplasmicfragment starting from Lys791 (VEGFR2, Genbank Accession No.L04947), acytoplasmic fragment starting from Lys398 (FGFR1, Genbank AccessionNo.X52833) and a cytoplasmic fragment starting from Lys558 (PDGFRβ,Genbank Accession No. M21616) in stead of HGFR in the above method. EGFRwas purchased from Sigma (Production No. E-2645).

2. Expression and Purification of Receptor Tyrosine Kinases

To the suspension of Sf9 cells (3×10⁸ cells) in SF-900II medium(purchased from Invitrogen) containing 2% FBS was added a solution ofHGFR transfected baculovirus above (4 ml), followed by a shaking cultureat 27° C. for 48 hrs. The cells infected with the HGFR transfectedbaculovirus were centrifuged at 1,000 rpm, 4° C. for 5 min to remove thesupernatant. The precipitated infected cells were suspended in 80 ml ofice-cold PBS, and centrifuged at 1,000 rpm, 4° C. for 5 min to removethe supernatant. The precipitated infected cells were suspended in 40 mlof ice-cold Lysis Buffer (50 mM Tris-HCl (pH 8.5), 5 mM2-mercaptoethanol, 100 mM KCl, 1 mM PMSF and 1% (v/v) NP-40). Thesuspension was centrifuged at 12,000 rpm, 4° C. for 30 min to provide asupernatant.

The supernatant was loaded onto an Ni-NTA agarose column (3 ml,purchased from Qiagen) equilibrated with 30 ml of Buffer A (20 mMTris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 500 mM KCl, 20 mM imidazoleand 10% (v/v) glycerol). The column was washed with 30 ml of Buffer A, 6ml of Buffer B (20 mM Tris-HCl (pH 8.5), 5 mM 2-mercaptoethanol, 1 MKCl, and 10% (v/v) glycerol) and 6 ml of Buffer A in this order. Then,the column was eluted with 6 ml of Buffer C (20 mM Tris-HCl (pH 8.5), 5mM 2-mercaptoethanol, 100 mM KCl, 100 mM imidazole, and 10% (v/v)glycerol) to provide a fraction. The fraction was entrapped in adialysis membrane (purchased from Spectrum Laboratories), dialyzed at 4°C. overnight with 1 L of dialysis buffer (20 mM Tris-HCl (pH 7.5), 10%(v/v) glycerol, 1 mM dithiothreitol, 0.1 mM Na₃VO₄ and 0.1 mM EGTA), andstored at −80° C. until used. An aliquot of the dialyzed fraction wassubjected to SDS electrophoresis, and then a recombinant protein(His6-HGFR, the HGFR cytoplasmic domain fused with six histidine at theN terminus) detected at a molecular weight of about 60 kDa when stainedwith Coomassie Brilliant Blue, was determined with regard to proteincontent using BSA (purchased from Sigma) as a standard. The VEGFR2cytoplasmic domain, the FGFR1 cytoplasmic domain, and the PDGFRβcytoplasmic domain were fused with six histidine at the N terminus bythe similar method to produce respective recombinant proteins(His6-VEGFR2, His6-FGFR1, and His6-PDGFRβ).

3. Assay for the Inhibitory Activity Against HGFR Tyrosine KinaseActivity

To each well of a 96-well round plate (purchased from NUNC, ProductionNo. 163320) were added 10 μl of a solution for kinase reaction (200 mMHepes (pH 7.4), 80 mM MgCl₂, 16 mM MnCl₂ and 2 mM Na₃VO₄), 250 ng ofbiotinylated poly(Glu4: Tyr1) (biotin-poly(GT), purchased from JapanSchering) (6 μl, 15-fold diluted with distilled water), 30 ng ofHis6-HGFR (10 μl, 60-fold diluted with 0.4% BSA) and a test substancedissolved in dimethylsulfoxide (4 μl, 100-fold diluted with 0.1% BSA) tomess up to 30 μl. To the well was added 10 μl of 4 μM ATP (purchasedfrom Sigma) diluted with distilled water to incubate at 30° C. for 10min, followed by adding 10 μl of 500 mM EDTA (pH 8.0) (purchased fromWako Pure Chemicals) to provide a kinase reaction solution.

The tyrosine-phosphorylated biotin-poly(GT) was detected using theHomogenous Time-Resolved Fluorescence (HTRF) method (AnalyticalBiochemistry, 269, 94-104, 1999). That is, to each well of a 96-wellhalf-area black plate (purchased from COSTAR, Production No. 3694) wereadded 20 μl of the above kinase reaction solution and 30 μl of adilution solution (50 mM Hepes (pH 7.4), 20 mM MgCl₂, 4 mM MnCl₂, 0.5 mMNa₃VO₄, 0.1% BSA and 100 mM EDTA). To the well was added 7.5 ng of aneuropium cryptate-labelled anti-phosphotyrosine antibody (Eu(K)-PY20,purchased from Japan Schering) (25 μl, 250-fold diluted with 20 mM Hepes(pH 7.0), 0.5 M KF and 0.1% BSA) and 250 ng of XL665-labelledstreptavidin (XL665-SA, purchased from Japan Schering) (25 μl, 62.5-folddiluted with 20 mM Hepes (pH 7.0), 0.5 M KF and 0.1% BSA), and using adiscovery HTRF microplate analyzer (Packard), the well was instantlyirradiated at an excitation wavelength of 337 nm to determinefluorescence intensities at 665 nm and 620 nm. The tyrosinephosphorylation rate of a biotin-poly(GT) was calculated using a delta F% value described in the text of a HTRF standard experiment method byJapan Schering. While defining the delta F % value of a well added withHis6-HGFR and no test substance as 100% and the delta F % value of awell added with no His6-HGFR and no test substance as 0%, ratio (%) ofthe delta F % value of each well added with the test substance wascalculated. The ratio (%) was used to calculate the concentration (IC₅₀)of the test substance necessary to inhibit HGFR kinase activity by 50%.The results are shown in Table 1.

TABLE 1 Example IC50 (μM) 1 0.066 2 0.055 3 0.039 4 0.045 5 0.06 6 0.647 0.051 8 0.048 9 0.053 10 0.054 11 0.046 12 0.037 13 0.055 14 0.06 150.053 16 0.064 17 0.048 18 0.053 19 0.061 20 0.059 21 0.062 22 0.05 230.045 24 0.048 25 0.085 26 0.058 27 0.059 28 0.072 29 0.063 30 0.044 310.062 32 0.05 33 0.026 34 0.073 35 0.029 36 0.046 37 0.053 38 0.052 390.1 40 0.055 41 0.044 42 0.057 43 0.18 44 0.091 45 0.24 46 0.064 470.083 48 0.063 49 0.18 51 0.25 52 0.16 53 0.27 54 0.064 55 0.12 56 0.1157 0.18 58 0.085 59 0.075 60 0.082 61 0.015 62 0.02 63 0.014 64 0.058 650.015 66 0.02 67 0.017 68 0.023 69 0.031 70 0.019 71 0.121 72 0.01 730.105 75 0.01 76 0.045 77 0.058 78 0.014 79 0.014 80 0.018 81 0.019 820.016 83 0.017 84 0.009 85 0.015 86 0.012 87 0.009 88 0.016 89 0.013 900.012 91 0.004 92 0.047 93 0.042 94 0.049 95 0.05 96 0.017 97 0.021 980.067 99 0.033 100 0.085 101 0.072 102 0.072 103 0.057 104 0.071 1050.015 106 0.016 107 0.0614. Assay for the Inhibitory Activity Against Receptor Tyrosine KinaseActivities Other than HGFR

The inhibitory activity against tyrosine kinase activities of VEGFR2,FGFR1, and EGFR were determined by the similar manner as in the assayfor the inhibitory activity against HGFR tyrosine kinase activitydescribed above, using 15 ng of His6-VEGFR2, 15 ng of His6-FGFR1 or 23ng of EGFR, respectively instead of HGFR. The inhibitory activityagainst PDGFRβ tyrosine kinase activity was evaluated by obtaining akinase reaction solution by the above method using 50 ng of His6-PDGFRβ,followed by detecting the tyrosine phosphorylated biotin-poly(GT) by amethod described below.

To each well of a 96-well streptavidin-coated plate (purchased fromPIERCE, Production No. 15129) were added 34 μl of the kinase reactionsolution and 16 μl of a dilution solution, followed by incubation atroom temperature for 30 min. Then, the well was washed three times with150 μl of a washing solution (20 mM Tris-HCl (pH 7.6), 137 mM NaCl,0.05% Tween-20 and 0.1% BSA), and to the well was added 70 μl ofanti-phosphotyrosine (PY20)—HRP conjugate (purchased from TransductionLaboratories, Production No. P-11625) (2.000-fold diluted with 20 mMTris-HCl (pH 7.6), 137 mM NaCl, 0.05% Tween-20 and 1% BSA), followed byincubation at room temperature for 1 hr. Then, each well was washedthree times with 150 μl of the washing solution, and supplied with 100μl of TMB Membrane Peroxidase Substrate (purchased from Funakoshi,Production No. 50-5077-03). After incubating the same at roomtemperature for 10 min, 100 μl of 1 M phosphoric acid was added to eachwell, and using a Plate Reader MTP-500 (Corona Electric), the absorbanceof the well was instantly determined at 450 nm. While defining theabsorbance of a well supplied with His6-PDGFRβ and no test substance as100% and the absorbance of a well supplied with no His6-PDGFRβ and notest substance as 0%, the absorbance ratio (%) of each well suppliedwith the test substance was calculated. The absorbance ratio (%) wasused to calculate the concentration (IC₅₀) of the test substancenecessary to inhibit PDGFRβ kinase activity by 50%.

Pharmacological Test Example 2 Inhibitory Activity Against theProliferation of Human Gastric Cancer Cells (MKN-45)

Human gastric cancer cells (MKN-45) were suspended in a 1%FBS-containing RPMI1640 medium (purchased from Sigma). The cellsuspension (1×10⁴ cells/ml) was added in a 96-well plate for cellculture (purchased from NUNC, Production No. 167008) at 0.1 ml/well, andthen cultured in a 5% CO₂ incubator (37° C.) overnight. After theculture, each well was supplied with 0.1 ml of a test substance dilutedwith a 1% FBS-containing RPMI1640 medium, followed by culturing in a 5%CO₂ incubator (37° C.) for 3 days. After the culture, each well wassupplied with 10 μl of Cell Counting Kit-8 (purchased from DOJINDO,Production No. 343-07623), followed by incubation in a 5% CO₂ incubator(37° C.) for about 1.5 hrs. After the incubation, using the Plate ReaderMTP-500 (Corona Electric), the absorbance of each well was determined ata measurement wavelength of 450 nm and a reference wavelength of 660 nm.The ratio (%) of absorbance of each well supplied with a test substanceto absorbance of the well supplied with no test substance wascalculated, and the ratio was used to calculate the concentration (IC₅₀)of the test substance necessary to inhibit the cell proliferation by50%. The results are shown in Table 2.

TABLE 2 Example IC50 (μM) 1 0.013 2 0.018 3 0.015 4 0.021 5 0.019 70.018 8 0.02 9 0.026 10 0.042 11 0.034 12 0.031 13 0.076 14 0.017 150.017 16 0.017 17 0.014 18 0.033 19 0.012 20 0.015 21 0.027 22 0.013 230.036 24 0.017 25 0.019 26 0.019 27 0.048 28 0.054 29 0.05 30 0.039 310.031 32 0.027 33 0.055 34 0.19 35 0.23 36 0.022 37 0.014 38 0.052 390.038 40 0.017 41 0.042 42 0.06 43 0.28 44 0.054 45 0.5 46 0.014 470.027 48 0.017 54 0.02 55 0.043 56 0.053 57 0.15 58 0.025 59 0.044 600.015 61 0.015 62 0.025 63 0.054 64 0.057 65 0.023 66 0.031 67 0.052 680.134 69 0.077 70 0.054 71 0.061 72 0.022 73 0.05 75 0.019 76 0.019 770.019 78 0.012 79 0.015 80 0.018 81 0.017 82 0.021 83 0.016 84 0.019 850.015 86 0.015 87 0.014 88 0.018 89 0.018 90 0.005 91 0.005 92 0.0049 930.0052 94 0.0049 95 0.0054 96 0.0038 97 0.038 98 0.023 99 0.018 1000.016 101 0.016 102 0.04 103 0.0058 104 0.0068 105 0.0041 106 0.046 1070.021

Pharmacological Test Example 3 Inhibitory Activity Against the HGFRAutophosphorylation Using ELISA

1. Preparation of Cell Extract

Human gastric cancer cells (MKN-45) were suspended in a 1%FBS-containing RPMI1640 medium (purchased from Sigma). The cellsuspension (1×10⁵ cells/ml) was put in a 96-well plate for cell culture(purchased from NUNC, Production No. 167008) at 0.1 ml/well, and thencultured in a 5% CO₂ incubator (37° C.) overnight. After the culture,from each well was removed the supernatant, followed by adding 0.05 mlof a 1% FBS-containing RPMI1640 medium. Then, the well was supplied with0.05 ml of the test substance dissolved in dimethyl sulfoxide (dilutedwith a 1% FBS-containing RPMI1640 medium), followed by culturing in a 5%CO₂ incubator (37° C.) for 1 hr. From each well was removed thesupernatant, and each well was washed with 150 μl of PBS, followed byadding 100 μl of a lysis buffer (50 mM Hepes (pH 7.4), 150 mM NaCl, 10%(v/v) glycerol, 1% Triton X-100, 1.5 mM MgCl₂, 1 mM EDTA (pH 8.0), 100mM NaF, 1 mM PMSF, 10 μg/ml Aprotinin, 50 μg/ml Leupeptin, 1 μg/mlPepstatin A and 1 mM Na₃VO₄). The plate was shaken at 4° C. for 1 hr toprepare the cell extract.

2. Preparation of an Anti-Phosphotyrosine Antibody-Immobilized Plate

To a 96-well plate for ELISA (purchased from COSTAR, Production No.3369) was added 50 μl of 60 mM bicarbonate buffer (pH 9.6) containing 50μg/ml of an anti-phosphotyrosine antibody (PY20, purchased fromTransduction Laboratory, Production No. P-11120). The plate wasincubated at 4° C. overnight.

3. Assay for Inhibitory Activity Against HGFR Autophosphorylation

Each well of the plate prepared in 2. was washed three times with 200 μlof PBS, and supplied with 150 μl of 3% BSA/PBS, followed by incubatingat room temperature for 2 hrs. Each well was washed three times with 200μl of PBS, and supplied with 50 μl of the above cell extract, followedby incubating at 4° C. overnight. After the incubation, each well waswashed three times with 250 μl of a washing solution (0.1% BSA, 20 mMTris-HCl (pH 7.6), 137 mM NaCl, and 0.05% Tween-20), and supplied with70 μl of anti-HGFR antibody (h-Met(C-12), purchased from Santa Cruz,Production No. sc-10) 2,000-fold diluted with a reaction solution (1%BSA, 20 mM Tris-HCl (pH 7.6), 137 mM NaCl and 0.05% Tween-20), followedby incubating at room temperature for 1 hr. The well was washed threetimes with 250 μl of the washing solution, and supplied with 70 μl ofperoxidase-labelled anti-rabbit IgG antibody (purchased from CellSignaling, Production No. 7074) 2,000-fold diluted with the reactionsolution, followed by incubating at room temperature for 1 hr. Each wellwas washed three times with 250 μl of the washing solution, and suppliedwith 70 μl of TMB Membrane Peroxidase Substrate (purchased fromFunakoshi, Production No. 50-5077-03), followed by incubating at roomtemperature for 10 min. Each well was supplied with 70 μl of 1 Mphosphoric acid, and using the Plate Reader MTP-500 (Corona Electric),the absorbance of the well was instantly determined at a measurementwavelength of 450 nm. While defining the absorbance of a well suppliedwith the cell extract having no test substance as 100% HGFRautophosphorylation activity, and the absorbance of a well supplied with50 μl of the lysis buffer as 0% HGFR autophosphorylation activity, theHGFR autophosphorylation activity (%) was calculated for each well. Theconcentration of the test substance was changed by several levels tocalculate HGFR autophosphorylation activities (%) in respective cases,and to calculate the concentration (IC₅₀) of the test substancenecessary to inhibit HGFR autophosphorylation activity by 50%. Theresults are shown in Table 3.

TABLE 3 Example IC50 (μM) 1 0.018 2 0.021 3 0.019 4 0.014 5 0.022 70.035 8 0.014 9 0.011 10 0.021 11 0.013 12 0.04 13 0.037 14 0.019 150.016 16 0.018 17 0.015 18 0.039 19 0.023 20 0.022 21 0.011 22 0.021 230.017 24 0.027 25 0.0046 26 0.0084 27 0.032 28 0.043 29 0.03 30 0.012 310.03 32 0.015 33 0.025 34 0.081 35 0.12 36 0.015 37 0.0066 38 0.018 390.016 40 0.008 41 0.016 42 0.042 43 0.33 44 0.08 45 0.44 46 0.019 470.03 48 0.012 49 0.26 51 0.38 52 0.17 53 0.37 54 0.024 55 0.016 56 0.04157 0.082 58 0.017 59 0.016 60 0.008 61 0.008 62 0.011 63 0.021 64 0.0265 0.01 66 0.013 67 0.01 68 0.071 69 0.037 70 0.027 71 0.011 72 0.01 730.008 75 0.013 76 0.03 77 0.013 78 0.015 79 0.016 80 0.014 81 0.007 820.022 83 0.018 84 0.017 85 0.014 86 0.011 87 0.012 88 0.02 89 0.017 900.011 91 0.0084 92 0.013 93 0.007 94 0.011 95 0.013 96 0.0042 97 0.01498 0.017 99 0.014 100 0.0094 101 0.015 102 0.041 103 0.012 104 0.015 1050.0086 106 0.039 107 0.036

Pharmacological Test Example 4 Inhibitory Activity Against Migration ofHuman Pancreatic Cancer Cells (SUIT-2)

Human pancreatic cancer cells (SUIT-2) were suspended in a 1%FBS-containing RPMI1640 medium (purchased from Sigma) to prepare a cellsuspension (8×10⁵ cells/ml). To the lower compartment of Transwell(purchased from COSTAR, Production No. 3422) was added 600 μl of a 1%FBS-containing RPMI1640 medium. To the upper compartment were added 50μl of the above cell suspension and 25 μl of the test substancedissolved in dimethyl sulfoxide (diluted with the 1% FBS-containingRPMI1640 medium), followed by culturing in a 5% CO₂ incubator (37° C.)for 1 hr. After the culture, to the upper compartment of each Transwellwas added 25 μl of human recombinant hepatocyte growth factor (HGF,purchased from Wako Pure Chemical Industry, Production No. 22949)diluted to 280 ng/ml with a 1% FBS-containing RPMI1640 medium, followedby culturing in a 5% CO₂ incubator (37° C.) for 24 hrs. The cellsadhering to the lower compartment of each well were counted in fivefields by a phase contrast microscope (200×) to calculate an averageadhering cell number. While defining the average adhering cell number ofa well supplied with HGF and no test substance as 100% cell migrationactivity and the average adhering cell number of a well supplied with noHGF and no test substance as 0% cell migration activity, the cellmigration activity percent (%) was calculated for each well. Theconcentration of the test substance was varied at several levels tocalculate the cell migration activity percent (%) for respective cases,and to calculate the concentration of the test substance necessary toinhibit the cell migration activity by 50% (IC₅₀).

Pharmacological Test Example 5 Inhibitory Activity Against the TumorGrowth of Human Gastric Cancer Cells (MKN-45)

Human gastric cancer cells (MNK-45) were suspended in HBSS (purchasedfrom GIBCO BRL). The cell suspension (5×10⁷ cells/ml) was transplantedunder the right flank skin of seven-week-old female BALB/c (nu/nu) miceat a volume of 0.1 ml. When tumor volume of the site transplanted withMNK-45 cells grew to 100-200 mm³, mice were grouped so that the groupsmight be equalized in average tumor volume. The test substance wassuspended in 0.5% methylcellulose, a mixed solution of hydrochloric acidand glucose (0.1N hydrochloric acid:5% glucose=1:9) or a mixed solutionof dimethyl sulfoxide-Tween-glucose (dimethyl sulfoxide:Tween 80:5%glucose (containing equimolar hydrochloric acid to the testsubstance)=7:13:80), were administered orally to the mice twice everyday. The tumor volumes were determined at the fifth day after theinitiation of the administration of the test substances. The major axisand the minor axis of tumor were measured by a caliper to calculate½×(major axis×minor axis×minor axis) for the tumor volume. Theexperiment was conducted using 10 mice in the control group(solvent-administered group) and 5 mice in test substance-administeredgroup. The ratio in tumor volume of the group for administrating thetest substance relative to that of the control group was defined as atumor proliferation rate (%). The results are shown in Table 4.

TABLE 4 Dose Tumor proliferation Example (mg/kg/time) rate (%) 2 30 73.32 100 27.5 8 30 53 8 100 23.3 12 30 73.9 12 100 27.6

Pharmacological Test Example 6 Inhibitory Activity Against Sandwich TubeFormation by Vascular Endothelial Cells Stimulated with HepatocyteGrowth Factor

Human umbilical vein endothelial cells (HUVECs) were isolated accordingto the reported method (Shin Seikagaku Jikken Koza, “Cell culturingtechniques”, p 197-202), and then cultured in a 5% CO₂ incubator (37°C.) using EGM-2 medium (purchased from Clonetics) until the cellsreached confluency.

To each well of a 24-well plate was added 0.4 ml of an ice-cold mixtureof collagen:5xRPMI1640:reconstitution buffer (all purchased from NittaGelatin, Inc.) at 7:2:1, followed by incubating in a 5% CO₂ incubator(37° C.) for 40 min to allow the solution to gell. Then, each well wassupplied with 1 ml of the cell suspension of HUVEC (1-1.2×10⁵ cells wereused, though the cell number varied slightly depending on the lot of theHUVEC to be used) diluted with a serum free medium for endothelial cellculture (SFM, purchased from GIBCO RBL) supplemented with 10 ng/ml ofEGF, followed by culturing in a 5% CO₂ incubator (37° C.) overnight. Thesupernatant was removed from each well, and then 0.4 ml of an ice-coldmixture of collagen:5×RPMI1640:reconstitution buffer (all purchased fromNitta Gelatin, Inc.) at 7:2:1 was layered on each well, followed byincubating in a 5% CO₂ incubator (37° C.) for 4 hours to allow thesolution to gell. To the upper compartment was added 1.5 ml of a SFMsolution containing 30 ng/ml of HGF (purchased from R&D), an angiogenicfactor, and a diluted test substance, followed by culturing in a 5% CO₂incubator (37° C.). On the fourth day after the addition of the testsubstance, the supernatant was removed from each well, and 0.4 ml of a3.3 mg/ml solution of MTT (purchased from Sigma) in PBS was added toeach well, followed by culturing in a 5% CO₂ incubator (37° C.) forabout 2 hours. The tube formed in the collagen gel of each well wasstained with MTT, and then the tube image was loaded in a computer(Macintosh) to determine the total length of the tube by an imageanalysis software “Angiogenesis quantification software” (purchased fromKurabo). The ratio of the total length of a tube formed in a wellsupplied with the test substance relative to a tube formed in a wellsupplied with no test substance was expressed as a percentage. The valueof the ratio was used to provide the concentration (IC₅₀) of the testsubstance necessary to inhibit the tube formation by 50%.

Pharmacological Test Example 7 Inhibitory Activity Against the Growth ofVascular Endothelial Cells by Stimulated with Hepatocyte Growth Factor

Human umbilical vein endothelial cells (HUVECs) were isolated accordingto the reported method (Shin Seikagaku Jikken Koza, “Cell culturingtechniques”, p 197-202), and then cultured in a 5% CO₂ incubator (37°C.) using EGM-2 medium (purchased from Clonetics) until the cellsreached confluency.

HUVECs were suspended in a serum-free medium for endothelial cellculture (SFM, purchased from GIBCO RBL) containing 2% FBS. The cellsuspension (2×10⁴ cells/ml) was put in a cell culturing 96-well plate(purchased from NUNC, Production No. 167008) at 0.1 ml/well, and thencultured in a 5% CO₂ incubator (37° C.) overnight. After the culture,each well was supplied with 50 μl of the test substance diluted with a2% FBS-containing serum-free medium for endothelial cell culture and 50μl of HGF (purchased from R&D) diluted at a concentration of 120 ng/mlwith a 2% FBS-containing serum-free medium for endothelial cell culture,followed by culturing in a 5% CO₂ incubator (37° C.). On the third dayafter the addition of the test substance, each well was supplied with 10μl of Cell Counting Kit-8 (purchased from DOJINDO, Production No.343-07623), and then the plate was incubated in a 5% CO₂ incubator (37°C.) for about 2 hours. After the incubation, using a Plate ReaderMTP-500 (Corona Electric), the absorbance of each well was determined ata measurement wavelength of 450 nm and a reference wavelength of 660 nm.While defining the absorbance of a well supplied with HGF and no testsubstance as 100% cell proliferation activity and the absorbance of thewell supplied with no test substance and no HGF as 0% cell proliferationactivity, the cell proliferation activity ratio (%) was calculated foreach cell. The concentration of the test substance was changed atseveral levels to calculate the cell proliferation activity ratio (%) inrespective cases, and to calculate the concentration (IC₅₀) of the testsubstance necessary to inhibit cell proliferation activity by 50%. Theresults are shown in Table 5.

TABLE 5 Example IC50 (μM) 1 0.0046 2 0.018 3 0.013 7 0.018 9 0.025 110.033 12 0.023 14 0.023 15 0.015 17 0.017 21 0.024

Chemical formulas of the compounds provided in Production Examples andExamples described above and Illustrative Examples are shown in Table 6to Table 18 below.

TABLE 6

Pro. Ex. 1

Pro. Ex. 2

Pro. Ex. 3

Pro. Ex. 4

Pro. Ex. 5

Pro. Ex. 6

Pro. Ex. 7

Pro. Ex. 8

Pro. Ex. 9

Pro. Ex. 10

Pro. Ex. 11

Pro. Ex. 12

Pro. Ex. 13

Pro. Ex. 14

Pro. Ex. 15

Pro. Ex. 16

Pro. Ex. 17

Pro. Ex. 18

Pro. Ex. 19

Pro. Ex. 20

Pro. Ex. 21

Pro. Ex. 22

Pro. Ex. 23

Pro. Ex. 24

Pro. Ex. 25

Pro. Ex. 26

Pro. Ex. 27

Pro. Ex. 28

Pro. Ex. 29

Pro. Ex. 30

Pro. Ex. 31

Pro. Ex. 32

Pro. Ex. 33

TABLE 7

Pro. Ex. 34

Pro. Ex. 35

Pro. Ex. 36

Pro. Ex. 37

Pro. Ex. 38

Pro. Ex. 39

Pro. Ex. 40

Pro. Ex. 41

Pro. Ex. 42

Pro. Ex. 43

Pro. Ex. 44

Pro. Ex. 45

Pro. Ex. 46

Pro. Ex. 47

Pro. Ex. 48

Pro. Ex. 49

Pro. Ex. 50

Pro. Ex. 51

Pro. Ex. 52

Pro. Ex. 53

Pro. Ex. 54

Pro. Ex. 55

Pro. Ex. 56

Pro. Ex. 57

Pro. Ex. 58

Pro. Ex. 59

Pro. Ex. 60

Pro. Ex. 61

TABLE 8

Example 1

Example 2

Example 3

Example 4

Example 5

Example 6

Example 7

Example 8

Example 9

Example 10

Example 11

Example 12

Example 13

Example 14

Example 15

Example 16

Example 17

Example 18

Example 19

Example 20

Example 21

TABLE 9

Example 22

Example 23

Example 24

Example 25

Example 26

Example 27

Example 28

Example 29

Example 30

Example 31

Example 32

Example 33

Example 34

Example 35

Example 36

Example 37

Example 38

Example 39

Example 40

Example 41

Example 42

TABLE 10

Example 43

Example 44

Example 45

Example 46

Example 47

Example 48

Example 49

Example 50

Example 51

Example 52

Example 53

Example 54

Example 55

Example 56

Example 57

Example 58

Example 59

Example 60

TABLE 11

Illustrative Example 1

Illustrative Example 2

Illustrative Example 3

Illustrative Example 4

Illustrative Example 5

Illustrative Example 6

Illustrative Example 7

Illustrative Example 8

Illustrative Example 9

Illustrative Example 10

Illustrative Example 11

Illustrative Example 12

Illustrative Example 13

Illustrative Example 14

Illustrative Example 15

Illustrative Example 16

Illustrative Example 17

Illustrative Example 18

TABLE 12

Illustrative Example 19

Illustrative Example 20

Illustrative Example 21

Illustrative Example 22

Illustrative Example 23

Illustrative Example 24

Illustrative Example 25

Illustrative Example 26

Illustrative Example 27

Illustrative Example 28

Illustrative Example 29

Illustrative Example 30

Illustrative Example 31

Illustrative Example 32

Illustrative Example 33

Illustrative Example 34

Illustrative Example 35

Illustrative Example 36

Illustrative Example 37

Illustrative Example 38

Illustrative Example 39

TABLE 13

Illustrative Example 40

Illustrative Example 41

Illustrative Example 42

Illustrative Example 43

Illustrative Example 44

Illustrative Example 45

Illustrative Example 46

Illustrative Example 47

TABLE 14

Pro. Ex. 62

Pro. Ex. 63

Pro. Ex. 64

Pro. Ex. 65

Pro. Ex. 66

Pro. Ex. 67

Pro. Ex. 68

Pro. Ex. 69

Pro. Ex. 70

Pro. Ex. 71

Pro. Ex. 72

Pro. Ex. 73

Pro. Ex. 74

Pro. Ex. 75

Pro. Ex. 76

Pro. Ex. 77

Pro. Ex. 78

Pro. Ex. 79

Pro. Ex. 80

Pro. Ex. 81

Pro. Ex. 82

Pro. Ex. 83

Pro. Ex. 84

Pro. Ex. 85

Pro. Ex. 86

Pro. Ex. 87

Pro. Ex. 88

Pro. Ex. 89

Pro. Ex. 90

Pro. Ex. 91

Pro. Ex. 92

Pro. Ex. 93

Pro. Ex. 94

TABLE 15

Pro. Ex. 95

Pro. Ex. 96

Pro. Ex. 97

Pro. Ex. 98

Pro. Ex. 99

Pro. Ex. 100

Pro. Ex. 101

Pro. Ex. 102

Pro. Ex. 103

Pro. Ex. 104

Pro. Ex. 105

Pro. Ex. 106

Pro. Ex. 107

Pro. Ex. 108

Pro. Ex. 109

Pro. Ex. 110

Pro. Ex. 111

Pro. Ex. 112

Pro. Ex. 113

Pro. Ex. 114

TABLE 16

Example 61

Example 62

Example 63

Example 64

Example 65

Example 66

Example 67

Example 68

Example 69

Example 70

Example 71

Example 72

Example 73

Example 75

Example 76

Example 77

Example 78

Example 79

Example 80

Example 81

TABLE 17

Example 82

Example 83

Example 84

Example 85

Example 86

Example 87

Example 88

Example 89

Example 90

Example 91

Example 92

Example 93

Example 94

Example 95

Example 96

TABLE 18

Example 97

Example 98

Example 99

Example 100

Example 101

Example 102

Example 103

Example 104

Example 105

Example 106

Example 107

Example 108

Example 109

Example 110

Example 111

Example 112

Example 113

Example 114

Example 115

Example 116

INDUSTRIAL APPLICABILITY

A compound according to the present invention has excellent HGFRinhibitory activity, and is useful as an anti-tumor agent againstvarious kinds of tumors such as a pancreatic cancer, a gastric cancer, acolorectal cancer, a breast cancer, a prostate cancer, a lung cancer, arenal cancer, a brain tumor and an ovarian cancer, an inhibitor againstangiogenesis or a cancer metastasis inhibitor.

1. A compound or a salt thereof, which is (1)N-[4-({2-[({4-[2-(Dimethylamino)ethyl]piperazin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(2)N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(3)N-(4-Fluorophenyl)-N′-{2-fluoro-4-[(2-{[(4-pyrrolidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}cyclopropane-1,1-dicarboxamide,(4)N-[4-({2-[({4-[(Dimethylamino)methyl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(5)N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]-2-fluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(6)N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(7)N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(8)N-(2-Fluoro-4-{[2-({[4-(1-methylpiperidin-4-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(9)N-(2-Fluoro-4-{[2-({[4-(1-methylazetidin-3-yl)piperazin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(10)N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(11)N-(4-[([2-({[4-(Azetidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(12)N-(4-Fluorophenyl)-N′-(2-fluoro-4-{[2-({[4-[(pyrrolidin-1-ylmethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)cyclopropane-1,1-dicarboxamide,(13)N-(4-{[2-({[(3S)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(14)N-(4-{[2-({[(3R)-3-(Dimethylamino)pyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(15)N-(2-Fluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,(16)N-(2-Fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,(17)N-[4-({2-[({4-[3-(Dimethylamino)azetidin-1-yl]piperidin-1-yl}-carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-phenylcyclopropane-1,1-dicarboxamide,(18)N-(4-{[2-({[(1-Ethylpiperidin-4-yl)(methyl)amino]carbonyl}amino)pyridin-4-yl]oxy}-2-fluorophenyl)-N′-phenylcyclopropane-1,1-dicarboxamide,(19)N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(20)N-(4-Fluorophenyl)-N′-[2-fluoro-4-({2-[pyrrolidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)phenyl]cyclopropane-1,1-dicarboxamide,(21)N-{2-Fluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(22)N-[4-({2-[(1,3′-Biazetidin-1′-ylcarbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(23)N-(2-Fluoro-4-{[2-({[3-[(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(24)N-(4-{[2-({[3-(Dimethylamino)azetidin-1-yl]carbonyl}amino)pyridin-4-yloxy}-2-fluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(25)N-[4-({2-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(26)N-{2-Fluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(27)N-(2-Fluoro-4-{[2-({[4-(hydroxymethyl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(28)N-(2-Fluoro-4-{[2-({[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(29)N-(2-Fluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(30)N-[4-({2-[(Azetidin-1-ylcarbonyl)amino]pyridin-4-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(31)N-{2,5-Difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(32)N-(2,5-Difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(33)N-[2,5-Difluoro-4-({2-[({3-[(dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)phenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(34)N-(2,5-Difluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(35)N-{4-[(2-{[3-(Azetidin-1-ylmethyl)azetidin-1-ylcarbonyl]amino}pyridin-4-yl)oxy]-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(36)N-(2,5-Difluoro-4-{[2-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(37)N-{2,5-Difluoro-4-[(4-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyrimidin-6-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(38)N-[4-({4-[({3-[(Dimethylamino)methyl]azetidin-1-yl}carbonyl)amino]pyrimidin-6-yl}oxy)-2,5-difluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(39)N-(2,5-Difluoro-4-{[4-({[3-(hydroxymethyl)azetidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxyphenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide, (40)N-(2,5-Difluoro-4-{[4-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(41)N-(2,5-Difluoro-4-{[4-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyrimidin-6-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(42)N-(4-{[2-({[4-(Dimethylamino)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}-2,5-difluorophenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(43)N-{2,5-Difluoro-4-[(2-{[(4-methylpiperazin-1-yl)carbonyl]amino}pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(44)N-{2,5-Difluoro-4-[(2-{[(4-hydroxypiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(45)N-{4-[(2-{[(4-Azetidin-1-ylpiperidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]oxy}-2,5-difluorophenyl}-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(46)N-(2,5-Difluoro-4-{[2-({[3-(2-dimethylaminoacetoxy)azetidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,(47) N-(2,5-Difluoro-4-{[2-({[(3S)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideor (48)N-(2,5-Difluoro-4-{[2-{[(3R)-3-hydroxypyrrolidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide.2. The compound of claim 1, which isN-[4-({2-[({4-[3-(dimethylamino)azetidin-1-yl]piperidin-1-yl}carbonyl)amino]pyridin-4-yl}oxy)-2-fluorophenyl]-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideor a salt thereof.
 3. The compound of claim 1, which isN-(2-fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamide,or a salt thereof.
 4. The compound of claim 1, which isN-{2,5-difluoro-4-[(2-{[(3-hydroxyazetidin-1-yl)carbonyl]amino}pyridin-4-yl)oxy]phenyl}-4-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideor a salt thereof.
 5. The compound of claim 1, which isN-(2,5-difluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideor a salt thereof.
 6. The compound of claim 1, which isN-(2,5-difluoro-4-{[2-({[methyl(1-methylpiperidin-4-yl)amino]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamideor a salt thereof.
 7. A salt of the compound of claim 3, which isN-(2-fluoro-4-{[2-({[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}amino)pyridin-4-yl]oxy}phenyl)-N′-(4-fluorophenyl)cyclopropane-1,1-dicarboxamidetartarate.